Pyrazole Derivatives as 11-Beta-HSD1 Inhibitors

ABSTRACT

A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     and pharmaceutically-acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are also described.

This application is a Continuation application of U.S. patentapplication Ser. No. 12/259,562, filed Oct. 28, 2008, now U.S. Pat. No.7,816,391, which is a Continuation Application of InternationalApplication No. PCT/GB2008/000454, filed Feb. 11, 2008, which claims thebenefit of U.S. Provisional Application No. 60/889,336, filed Feb. 12,2007, and U.S. Provisional Application No. 60/985,735, filed Nov. 6,2007, all of which are hereby incorporated by reference in theirentirety.

This invention relates to chemical compounds, orpharmaceutically-acceptable salts to thereof. These compounds possesshuman 11-β-hydroxysteroid dehydrogenase type 1 enzyme (11βHSD1)inhibitory activity and accordingly have value in the treatment ofdisease states including metabolic syndrome and are useful in methods oftreatment of a warm-blooded animal, such as man. The invention alsorelates to processes for the manufacture of said compounds, topharmaceutical compositions containing them and to their use in themanufacture of medicaments to inhibit 11βHSD1 in a warm-blooded animal,such as man.

Glucocorticoids (cortisol in man, corticosterone in rodents) are counterregulatory hormones i.e. they oppose the actions of insulin (Dallman MF, Strack A M, Akana S F et al. 1993; Front Neuroendocrinol 14,303-347). They regulate the expression of hepatic enzymes involved ingluconeogenesis and increase substrate supply by releasing glycerol fromadipose tissue (increased lipolysis) and amino acids from muscle(decreased protein synthesis and increased protein degradation).Glucocorticoids are also important in the differentiation ofpre-adipocytes into mature adipocytes which are able to storetriglycerides (Bujalska I J et al. 1999; Endocrinology 140, 3188-3196).This may be critical in disease states where glucocorticoids induced by“stress” are associated with central obesity which itself is a strongrisk factor for type 2 diabetes, hypertension and cardiovascular disease(Bjorntorp P & Rosmond R 2000; Int. J. Obesity 24, S80-S85).

It is now well established that glucocorticoid activity is controllednot simply by secretion of cortisol but also at the tissue level byintracellular interconversion of active cortisol and inactive cortisoneby the 11-beta hydroxysteroid dehydrogenases, 11βHSD1 (which activatescortisone) and 11βHSD2 (which inactivates cortisol) (Sandeep T C &Walker B R 2001 Trends in Endocrinol & Metab. 12, 446-453). That thismechanism may be important in man was initially shown usingcarbenoxolone (an anti-ulcer drug which inhibits both 11βHSD1 and 2)treatment which (Walker B R et al. 1995; J. Clin. Endocrinol. Metab. 80,3155-3159) leads to increased insulin sensitivity indicating that11βHSD1 may well be regulating the effects of insulin by decreasingtissue levels of active glucocorticoids (Walker B R et al. 1995; J.Clin. Endocrinol. Metab. 80, 3155-3159).

Clinically, Cushing's syndrome is associated with cortisol excess whichin turn is associated with glucose intolerance, central obesity (causedby stimulation of pre-adipocyte differentiation in this depot),dyslipidaemia and hypertension. Cushing's to syndrome shows a number ofclear parallels with metabolic syndrome. Even though the metabolicsyndrome is not generally associated with excess circulating cortisollevels (Jessop D S et al. 2001; J. Clin. Endocrinol. Metab. 86,4109-4114) abnormally high 11βHSD1 activity within tissues would beexpected to have the same effect. In obese men it was shown that despitehaving similar or lower plasma cortisol levels than lean controls,11βHSD1 activity in subcutaneous fat was greatly enhanced (Rask E et al.2001; J. Clin. Endocrinol. Metab. 1418-1421). Furthermore, the centralfat, associated with the metabolic syndrome expresses much higher levelsof 11βHSD1 activity than subcutaneous fat (Bujalska I J et al. 1997;Lancet 349, 1210-1213). Thus there appears to be a link betweenglucocorticoids, 11βHSD1 and the metabolic syndrome.

11βHSD1 knock-out mice show attenuated glucocorticoid-induced activationof gluconeogenic enzymes in response to fasting and lower plasma glucoselevels in response to stress or obesity (Kotelevtsev Y et al. 1997;Proc. Natl. Acad. Sci. USA 94, 14924-14929) indicating the utility ofinhibition of 11βHSD1 in lowering of plasma glucose and hepatic glucoseoutput in type 2 diabetes. Furthermore, these mice express ananti-atherogenic lipoprotein profile, having low triglycerides,increased HDL cholesterol and increased apo-lipoprotein AI levels.(Morton N M et al. 2001; J. Biol. Chem. 276, 41293-41300). Thisphenotype is due to an increased hepatic expression of enzymes of fatcatabolism and PPARα. Again this indicates the utility of 11βHSD1inhibition in treatment of the dyslipidaemia of the metabolic syndrome.

The most convincing demonstration of a link between the metabolicsyndrome and 11βHSD1 comes from recent studies of transgenic miceover-expressing 11βHSD1 (Masuzaki H et al. 2001; Science 294,2166-2170). When expressed under the control of an adipose specificpromoter, 11βHSD1 transgenic mice have high adipose levels ofcorticosterone, central obesity, insulin resistant diabetes,hyperlipidaemia and hyperphagia. Most importantly, the increased levelsof 11βHSD1 activity in the fat of these mice are similar to those seenin obese subjects. Hepatic 11βHSD1 activity and plasma corticosteronelevels were normal, however, hepatic portal vein levels ofcorticosterone were increased 3 fold and it is thought that this is thecause of the metabolic effects in liver.

Overall it is now clear that the complete metabolic syndrome can bemimicked in mice simply by overexpressing 11βHSD1 in fat alone at levelssimilar to those in obese man.

11βHSD1 tissue distribution is widespread and overlapping with that ofthe glucocorticoid receptor. Thus, 11βHSD1 inhibition could potentiallyoppose the effects of glucocorticoids in a number ofphysiological/pathological roles. 11βHSD1 is present in human skeletalmuscle and glucocorticoid opposition to the anabolic effects of insulinon protein turnover and glucose metabolism are well documented (WhorwoodC B et al. 2001; J. Clin. Endocrinol. Metab. 86, 2296-2308). Skeletalmuscle must therefore be an important target for 11βHSD1 based therapy.

Glucocorticoids also decrease insulin secretion and this couldexacerbate the effects of glucocorticoid induced insulin resistance.Pancreatic islets express 11βHSD1 and carbenoxolone can inhibit theeffects of 11-dehydrocorticosterone on insulin release (Davani B et al.2000; J. Biol. Chem. 275, 34841-34844). Thus in treatment of diabetes11βHSD1 inhibitors may not only act at the tissue level on insulinresistance but also increase insulin secretion itself.

Skeletal development and bone function is also regulated byglucocorticoid action. 11βHSD1 is present in human bone osteoclasts andosteoblasts and treatment of healthy volunteers with carbenoxoloneshowed a decrease in bone resorption markers with no change in boneformation markers (Cooper M S et al 2000; Bone 27, 375-381). Inhibitionof 11βHSD1 activity in bone could be used as a protective mechanism intreatment of osteoporosis.

Glucocorticoids may also be involved in diseases of the eye such asglaucoma. 11βHSD1 has been shown to affect intraocular pressure in manand inhibition of 11βHSD1 may be expected to alleviate the increasedintraocular pressure associated with glaucoma (Rauz S et al. 2001;Investigative Ophthalmology & Visual Science 42, 2037-2042).

There appears to be a convincing link between 11βHSD1 and the metabolicsyndrome both in rodents and in humans. Evidence suggests that a drugwhich specifically inhibits 11βHSD1 in type 2 obese diabetic patientswill lower blood glucose by reducing hepatic gluconeogenesis, reducecentral obesity, improve the atherogenic lipoprotein phenotype, lowerblood pressure and reduce insulin resistance. Insulin effects in musclewill be enhanced and insulin secretion from the beta cells of the isletmay also be increased.

Currently there are two main recognised definitions of metabolicsyndrome.

1) The Adult Treatment Panel (ATP III 2001 JMA) definition of metabolicsyndrome indicates that it is present if the patient has three or moreof the following symptoms:Waist measuring at least 40 inches (102 cm) for men, 35 inches (88 cm)for women;Serum triglyceride levels of at least 150 mg/dl (1.69 mmol/l);HDL cholesterol levels of less than 40 mg/dl (1.04 mmol/l) in men, lessthan 50 mg/dl (1.29 mmol/l) in women;Blood pressure of at least 135/80 mm Hg; and/or Blood sugar (serumglucose) of at least 110 mg/dl (6.1 mmol/l).2) The WHO consultation has recommended the following definition whichdoes not imply causal relationships and is suggested as a workingdefinition to be improved upon in due course:The patient has at least one of the following conditions: glucoseintolerance, impaired glucose tolerance (IGT) or diabetes mellitusand/or insulin resistance; together with two or more of the following:

Raised Arterial Pressure;

Raised plasma triglycerides

Central Obesity Microalbuminuria

We have found that the compounds defined in the present invention, or apharmaceutically-acceptable salt thereof, are effective 11βHSD1inhibitors, and accordingly have value in the treatment of diseasestates associated with metabolic syndrome. We have also found that thecompounds of the invention have improved properties, which would makethem better candidates for use as pharmaceuticals. For example, ingeneral the compounds of the invention have good oral bioavailabilitywhilst retaining potency. Therefore this group of compounds would beexpected to provide superior oral exposure at a lower dose and therebybe particularly suitable for use in the treatment or prevention of adisease or medical condition treatable by inhibiting 11βHSD1.

The compounds of the invention may also have superior potency and/oradvantageous physical properties and/or favourable toxicity profilesand/or favourable metabolic profiles in comparison with other 11βHSD1inhibitors known in the art. For example, in general the compounds ofthe present invention have acceptable free drug levels as measured byplasma protein binding experiments.

Accordingly there is provided a compound of formula (1):

wherein:Q is O, S or a single bond;R¹ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, heterocyclyl,arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₃₋₇cycloalkylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl or C₃₋₇cycloalkylC₂₋₃alkynyl, [each of whichis optionally substituted by 1, 2 or 3 substituents independentlyselected from C₁₋₃alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl,C₁₋₃alkoxy, C₁₋₃alkylS(O)_(n)— (wherein n is 0, 1, 2 or 3),R⁵CON(R^(5′))—, (R^(5′))(R^(5″))NC(O)—, R^(5′)C(O)O—, R^(5′)OC(O)—,(R^(5′))(R^(5″))NC(O)N(R^(5″′))—, R⁵SO₂N(R^(5″))—, and(R^(5′))(R^(5″))NSO₂— (wherein R⁵ is C₁₋₃alkyl optionally substituted by1, 2 or 3 substituents selected from hydroxyl, halo or cyano; andR^(5′) and R^(5″) are independently selected from hydrogen and C₁₋₃alkyloptionally substituted by 1, 2 or 3 substituents independently selectedfrom hydroxyl, halo, C₁₋₃alkoxy, carboxy and cyano or R^(5′) and R^(5″)together with the nitrogen atom to which they are attached form a 4-7membered saturated ring)];R² is selected from heterocyclyl, C₃₋₇cycloalkyl(CH₂)_(m)—, andC₆₋₁₂polycycloalkyl(CH₂)_(m)— (wherein m is 0, 1 or 2 and the rings areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R⁶);R³ is selected from hydrogen, C₁₋₄alkyl C₃₋₅cycloalkyl andC₃₋₅cycloalkylmethyl (each of which is optionally substituted by 1, 2 or3 fluoro atoms);R² and R³ together with the nitrogen atom to which they are attachedform a saturated mono, bicyclic or bridged ring system optionallycontaining 1 or 2 additional ring heteroatoms selected from nitrogen,oxygen and sulphur and which is optionally fused to a saturated,partially saturated or unsaturated monocyclic ring wherein the resultingring system is optionally substituted by 1, 2, or 3 substituentsindependently selected from R⁷;R⁶ and R⁷ are independently selected from hydroxyl, halo, oxo, carboxy,cyano, trifluoromethyl, R⁹, R⁹O—, R⁹CO—, R⁹C(O)O—, R⁹CON(R^(9′))—,(R^(9′))(R⁹″)NC(O)—, (R^(9′))(R⁹″)N—, R⁹S(O)_(a)— wherein a is 0 to 2,R^(9′)OC(O)—, (R^(9′))(R⁹″)NSO₂—, R⁹SO₂N(R^(9″))—,(R^(9′))(R^(9″))NC(O)N(R^(9′″))—, phenyl and heteroaryl [wherein thephenyl and heteroaryl groups are optionally fused to a phenyl,heteroaryl or a saturated or partially-saturated 5- or 6-membered ringoptionally containing 1, 2 or 3 heteroatoms independently selected fromnitrogen, oxygen and sulphur and the resulting ring system is optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₄alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino,di-N,N—(C₁₋₄alkyl)amino, N—C₁₋₄alkylcarbamoyl,di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(r)—,C₁₋₄alkylS(O)_(r)C₁₋₄alkyl (wherein r is 0, 1 or 2)];R⁹ is independently selected from C₁₋₃alkyl optionally substituted byhydroxyl, halo, C₁₋₄alkoxy, carboxy or cyano;R^(9′), R^(9″) and R^(9″′) are independently selected from hydrogen andC₁₋₃alkyl optionally substituted by 1, 2, or 3 substituentsindependently selected from hydroxyl, halo, C₁₋₄alkoxy, carboxy andcyano);A is a phenyl or heteroaryl ring (the phenyl or heteroaryl ring beingoptionally substituted on ring carbon atoms by 1, 2 or 3 R¹⁰ groups andon an available ring nitrogen in a heteroaryl group by R¹¹);R¹⁰ is independently selected from C₁₋₄alkyl, hydroxyl, cyano,trifluoromethyl, trifluoromethoxy, halo, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino, di-N,N—(C₁₋₄alkyl)amino,N—C₁₋₄alkylcarbamoyl, di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(s)—,C₁₋₄alkylS(O)_(s)C₁₋₄alkyl (wherein s is 0, 1 or 2)];R¹¹ is independently C₁₋₃alkyl optionally substituted by 1, 2 or 3fluoro atoms;X is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹²)(R¹³)—, —C(R¹²)(R¹³)C(R¹⁴)(R¹⁵)—, —CH₂O— or —CH₂S(O)_(t)—(wherein t is 0, 1 or 2):Y is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹⁶)(R¹⁷)— or —C(R¹⁸)(R¹⁹)C(R²⁰)(R²¹)—;wherein R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ areindependently selected from hydrogen and methyl;or a pharmaceutically-acceptable salt thereof.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₄alkyl” includes propyl, isopropyl and t-butyl. However,references to individual alkyl groups such as “propyl” are specific forthe straight chain version only and references to individual branchedchain alkyl groups such as “isopropyl” are specific for the branchedchain version only. A similar convention applies to other radicalstherefore “C₁₋₄alkoxyC₁₋₄alkyl” would include 1-(C₁₋₄alkoxy)propyl,2-(C₁₋₄alkoxy)ethyl and 3-(C₁₋₄alkoxy)butyl. The term “halo” refers tofluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A 4-7 membered saturated ring (for example formed between R^(5′) andR^(5″) and the nitrogen atom to which they are attached) is a monocyclicring containing the nitrogen atom as the only ring atom.

“Heteroaryl”, unless otherwise specified, is a totally unsaturated,monocyclic ring containing 5 or 6 atoms of which at least 1, 2 or 3 ringatoms are independently chosen from nitrogen, sulphur or oxygen, whichmay, unless otherwise specified, be carbon-linked. A ring nitrogen atommay be optionally oxidised to form the corresponding N-oxide. Examplesand suitable values of the term “heteroaryl” are thienyl, furyl,thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl,isothiazolyl, triazolyl, pyrimidyl, to pyrazinyl, pyridazinyl andpyridyl. Particularly “heteroaryl” refers to thienyl, furyl, thiazolyl,pyridyl, imidazolyl or pyrazolyl.

“Heterocycyl” is a 4-7 saturated, monocyclic ring having 1-3 ringheteroatoms selected from nitrogen, oxygen and sulphur. The ring sulphurmay be optionally oxidised to SO₂.

A C₃₋₇cycloalkyl ring is a saturated carbon ring containing from 3 to 7ring atoms.

A C₃₋₄cycloalkandiyl ring is a saturated carbon ring containing 3 or 4ring atoms. It is a diradical with the radicals on different ring carbonatoms.

A C₃₋₄cycloalkanylidene ring is a saturated carbon ring containing 3 or4 ring atoms. It is a diradical with the radicals on the same ringcarbon atom.

A polycycloalkyl ring is a ring system in which either at least 2 ringsare fused together or in which 2 ring have one ring atom in common(spiro).

A “saturated mono, bicyclic or bridged ring system optionally containing1 or 2 additional ring heteroatoms selected from nitrogen, oxygen andsulphur”, unless otherwise specified contains 4-14 ring atoms.Particularly a mono ring contains 4-7 ring atoms, a bicyclic ring 6-14ring atoms and a bridged ring system 6-14 ring atoms. Examples of monorings include piperidinyl, piperazinyl and morpholinyl. Examples ofbicyclic rings include decalin and2,3,3a,4,5,6,7,7a-octahydro-1H-indene.

Bridged ring systems are ring systems in which there are two or morebonds common to two or more constituent rings. Examples of bridged ringsystems include 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane,2-aza-bicyclo[2.2.1]heptane and 7-azabicyclo(2,2,1)heptane, 1- and2-adamantanyl.

A “saturated, partially saturated or unsaturated monocyclic ring” is,unless otherwise specified, a 4-7 membered ring. Examples include,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl and phenyl.

Examples of a “saturated or partially-saturated 5- or 6-membered ringoptionally containing 1, 2 or 3 heteroatoms independently selected fromnitrogen, oxygen and sulphur” include piperidinyl, piperazinyl andmorpholinyl.

Examples of “C₁₋₄alkoxy” include methoxy, ethoxy and propoxy. Examplesof “C₁₋₄alkoxyC₁₋₄alkyl” include methoxymethyl, ethoxymethyl,propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 2-propoxyethyl.Examples of “C₁₋₄alkylS(O)_(n) wherein n is 0 to 2” include methylthio,ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.Examples of “C₁₋₄alkylS(O)_(q)C₁₋₄alkyl” wherein q is 0 to 2” includemethylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl,ethylsulphonyl, methylthiomethyl, ethylthiomethyl,methylsulphinylmethyl, ethylsulphinylmethyl, mesylmethyl andethylsulphonylmethyl. Examples of “C₁₋₄alkanoyl” include propionyl andacetyl. Examples of “N—(C₁₋₄alkyl)amino” include methylamino andethylamino. Examples of “N,N—(C₁₋₄alkyl)₂ amino” includeN,N-dimethylamino, N,N-diethylamino and N-ethyl-N-methylamino. Examplesof “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl. Examples of“C₂₋₄alkynyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of“N—(C₁₋₄alkyl)carbamoyl” are methylaminocarbonyl and ethylaminocarbonyl.Examples of “N,N—(C₁₋₄alkyl)₂ carbamoyl” are dimethylaminocarbonyl andmethylethylaminocarbonyl. Examples of “C₃₋₇cycloalkylC₁₋₃alkalkyl”include cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl,cyclopentylmethyl and cyclohexylmethyl. Examples of“C₃₋₇cycloalkylC₂₋₃alkalkenyl” include 2-cyclopropylethenyl,2-cyclopentylethenyl and 2-cyclohexylethenyl. Examples of“C₃₋₇cycloalkylC₂₋₃alkalkynyl” include 2-cyclopropylethynyl,2-cyclopentylethynyl and 2-cyclohexylethynyl.

Examples of “C₃₋₇cycloalkyl(CH₂)_(m)—” include cyclopropymethyl,2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl. Examples of C₆₋₁₂polycycloalkyl(CH₂)_(m)— includenorbornyl bicyclo[2.2.2]octane(CH₂)_(m)—, bicyclo[3.2.1]octane(CH₂)_(m)—and 1- and 2-adamantanyl(CH₂)_(m)—.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a physiologically-acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Some compounds of the formula (1) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess 11βHSD1 inhibitoryactivity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (1) that possess 11βHSD1 inhibitory activity.

It is also to be understood that certain compounds of the formula (1)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms, which possess 11βHSD1 inhibitory activity.

The invention also relates to in vivo hydrolysable esters of a compoundof the formula (I). In vivo hydrolysable esters are those esters thatare broken down in the animal body to produce the parent carboxylicacid.

In one embodiment of the invention are provided compounds of formula(1). In an alternative embodiment are providedpharmaceutically-acceptable salts of compounds of formula (1).

In one aspect of the invention, there is provided a compound of theformula (Ia):

wherein R¹, R² and R³ are as hereinabove defined and R¹⁰ is selectedfrom hydrogen, C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy and C₁₋₄alkylS—.In another aspect R¹⁰ is selected from hydrogen, methyl,trifluoromethyl, methoxy and methylthio. In another aspect R¹⁰ ishydrogen.

In another aspect of the invention, there is provided a compound of theformula (Ib):

wherein R¹, R² and R³ are as hereinabove defined and R¹⁰ is selectedfrom hydrogen, C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy and C₁₋₄alkylS—.In another aspect R¹⁰ is selected from hydrogen, methyl,trifluoromethyl, methoxy and methylthio. In another aspect R¹⁰ ishydrogen.

Particular values of variable groups are as follows. Such values may beused where appropriate with any of the definitions, claims orembodiments defined hereinbefore or hereinafter, for compounds offormula (1). The definitions of R¹, R² and R³ and variables within thosegroups may be used for the compound of formula (Ia):

Definition of Q

a) In one aspect, the invention relates to a compound of the formula (I)as hereinabove defined wherein Q is O.b) In another aspect Q is S.c) In another aspect Q is a single bond.

Definition of R¹

a) In one aspect R¹ is C₃₋₆cycloalkyl optionally substituted by 1, 2 or3 substituents independently selected from C₁₋₃alkyl, hydroxy, halo,oxo, cyano, fluoro, trifluoromethyl and C₁₋₃alkoxy.b) In another aspect R¹ is C₃₋₆cycloalkyl.c) In another aspect R¹ is C₃₋₆cycloalkylC₁₋₂alkyl optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₃alkyl, hydroxy, halo, oxo, cyano, fluoro, trifluoromethyl andC₁₋₃alkoxy.d) In another aspect R¹ is C₃₋₄cycloalkylC₁₋₂alkyl.e) In another aspect R¹ is C₁₋₄alkyl optionally substituted by 1, 2 or 3substituents independently selected from C₁₋₃alkyl, hydroxy, halo, oxo,cyano, trifluoromethyl and C₁₋₃alkoxy.f) In another aspect R¹ is C₁₋₄alkyl.g) In another aspect R¹ is propyl optionally substituted by 1 or 2substituents independently selected from C₁₋₃alkyl, hydroxy, halo, oxo,cyano, trifluoromethyl and C₁₋₃alkoxy.h) In another aspect R¹ is propyl.

Definition of R²

a) In one aspect, R² is selected from C₃₋₇cycloalkyl(CH₂)_(m)—, andC₆₋₁₂polycycloalkyl(CH₂)_(m)— (wherein m is 0, 1 or 2 and the rings areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R⁶) wherein m is 0, 1 or 2.b) In another aspect, R² is selected from C₅₋₇cycloalkyl(CH₂)_(m)— andC₈₋₁₂polycycloalkyl(CH₂)_(m)— (wherein the rings are optionallysubstituted by 1, 2 or 3 substituents independently selected from R⁶)and wherein m is 0, 1 or 2.c) In another aspect, R² is selected from C₅₋₇cycloalkyl(CH₂)_(m)—,C₇₋₁₀bicycloalkyl(CH₂)_(m)— and C₁₀tricycloalkyl(CH₂)_(m)— (wherein thecycloalkyl, bicycloalkyl and tricycloalkyl rings are optionallysubstituted by 1, 2 or 3 substituents independently selected from R⁶)and wherein m is 0, 1 or 2.d) In yet another aspect, R² is selected from C₅₋₇cycloalkyl(CH₂)_(m)—,C₇₋₁₀bicycloalkyl(CH₂)_(m)— and adamantyl (wherein the cycloalkyl,bicycloalkyl and tricycloalkyl rings are optionally substituted by 1, 2or 3 substituents independently selected from R⁶) and wherein m is 0, 1or 2.

Definition of m

a) In one aspect, m is 0 or 1.

Definition of R³

a) In one aspect, R³ is C₁₋₄alkyl.b) In another aspect, R³ is hydrogen, methyl or ethyl.c) In another aspect, R³ is hydrogen.d) In another aspect, R³ is methyl.e) In another aspect, R³ is ethyl.f) In another aspect, R³ is cyclopropyl.

Definition of R² and R³ Together

a) In another aspect, R² and R³ together with the nitrogen atom to whichthey are attached form a saturated 5 or 6-membered mono, 6-12 memberedbicyclic or 6-12 membered bridged ring system optionally containing 1 or2 additional ring heteroatoms selected from nitrogen, oxygen and sulphurand which is optionally fused to a saturated, partially-saturated oraryl monocyclic ring wherein the resulting ring system is optionallysubstituted by 1, 2, or 3 substituents independently selected from R⁷.

Definition of R⁶

a) In one aspect, R⁶ is independently selected from hydroxyl, R⁹O—,R⁹CO— and R⁹C(O)O—wherein R⁹ is as hereinabove defined.b) In another aspect, R⁶ is independently selected from hydroxyl, R⁹O—,R⁹CO— and R⁹C(O)O—wherein R⁹ is C₁₋₃alkyl optionally substituted by C₁₋₄alkoxy or carboxy.c) In another aspect, R⁶ is independently selected from R⁹CON(R^(9′))—,R⁹SO₂N(R^(9″))— and (R^(9′))(R^(9″))NC(O)N(R^(9′″))—;wherein R⁹ is as hereinabove defined.d) In another aspect, R⁶ is independently selected from R⁹CON(R^(9′))—,R⁹SO₂N(R^(9″))— and (R^(9′))(R^(9″))NC(O)N(R^(9′″))—;R⁹ is C₁₋₃alkyl optionally substituted by C₁₋₄alkoxy or carboxy;R^(9′), R^(9″) and R^(9′″) are independently selected from hydrogen andC₁₋₃alkyl optionally substituted by C₁₋₄alkoxy or carboxy).e) In another aspect, R⁶ is independently selected from(R^(9′))(R⁹″)NC(O)— and (R^(9′))(R⁹″)N—;wherein R^(9′) and R^(9″) are as hereinabove defined.f) In another aspect, R⁶ is independently selected from(R^(9′))(R⁹″)NC(O)— and (R^(9′))(R⁹″)N—;wherein R^(9′) and R^(9″) are independently selected from hydrogen andC₁₋₃alkyl optionally substituted by C₁₋₄alkoxy or carboxy.g) In one aspect R⁶ is selected from methyl, trifluoromethyl, chloro,fluoro, bromo, methoxy, ethoxy, trifluoromethoxy, methanesulfonyl,ethanesulfonyl, methylthio, ethylthio, amino, N-methylamino,N-ethylamino, N-propylamino, N,N-dimethylamino, N,N-methylethylamino orN,N-diethylamino.h) In another aspect, R⁶ is optionally substituted phenyl, pyridyl orpyrimidyl.i) In another aspect, R⁶ is optionally substituted pyrid-2-yl,pyrid-3-yl or pyrid-4-yl.

Definition of R⁷

a) In another aspect, R⁷ is independently selected from hydroxyl, halo,oxo, cyano, trifluoromethyl, R⁹ and R⁹O— (wherein R⁹ is as hereinabovedefined).b) In another aspect, R⁷ is independently selected from hydroxyl, halo,trifluoromethyl, R⁹ and R⁹O— (wherein R⁹ is as hereinabove defined).

Definition of R⁹

a) In one aspect, R⁹ is independently selected from C₁₋₃alkyl.

Definition of R^(9′), R^(9″) and R^(9′″),

a) In one aspect, R^(9′), R^(9″) and R^(9′″) are independently selectedfrom hydrogen and C₁₋₃alkyl.

Definition of Y

a) In one aspect, Y is independently selected from direct bond, —CH₂—and —CH₂CH₂—.b) In one aspect, Y is independently selected from —CH₂— and —CH₂CH₂—.c) In another aspect Y is a direct bond.

Definition of A

a) In one aspect A is phenyl optionally substituted by R¹⁰.b) In another aspect A is heteroaryl optionally substituted by R¹⁰ andR¹¹.c) In another aspect A is thienyl optionally substituted by R¹⁰ and R¹¹.d) In another aspect A is pyridyl optionally substituted by R¹⁰ and R¹¹.e) In another aspect A is phen-1,4-diyl

Definition of R¹⁰

a) In one aspect, R¹⁰ is independently selected from C₁₋₄alkyl,hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy,halo, C₁₋₄alkoxy and C₁₋₄alkoxyC₁₋₄alkyl.b) In another aspect, R¹⁰ is independently selected from methyl, ethyl,hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy,halo, methoxy, ethoxy, methoxymethyl and ethoxymethyl.c) In another aspect, R¹⁰ is independently selected from methyl, ethyl,cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, halo,methoxy, ethoxy.

Definition of R¹¹

a) In one aspect, R¹¹, is independently selected from C₁₋₃alkyl,trifluoromethyl and difluoromethyl.b) In one aspect, R¹¹, is independently selected from methyl, ethyl,trifluoromethyl and difluoromethyl.

Definition of X

a) In one aspect, X is independently selected from direct bond, —CH₂—,—CHMe-, —CMe₂-, —CH₂CH₂—, —CH₂O— and —CH₂S—.b) In one aspect, X is independently selected from —CH₂—, —CHMe-,—CMe₂-, —CH₂CH₂—, —CH₂O— and —CH₂S—.c) In another aspect X is independently selected fromcyclopropanylidene, cyclobutanylidene, cyclopropane-1,2-diyl andcyclobutan-1,2-diyl.d) In another aspect X is a direct bond.In one aspect, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ arehydrogen.In one aspect R¹ is optionally substituted by 0 substituents.In one aspect R¹ is optionally substituted by 1 substituent.In one aspect R¹ is optionally substituted by 2 substituents.In one aspect R¹ is optionally substituted by 3 substituents.In one aspect R² is optionally substituted by 0 substituents.In one aspect R² is optionally substituted by 1 substituent.In one aspect R² is optionally substituted by 2 substituents.In one aspect R² is optionally substituted by 3 substituents.In one aspect R³ is optionally substituted by 0 substituents.In one aspect R³ is optionally substituted by 1 substituent.In one aspect R³ is optionally substituted by 2 substituents.In one aspect R³ is optionally substituted by 3 substituents.In one aspect the group formed by R² and R³ together is optionallysubstituted by 0 substituents.In one aspect the group formed by R² and R³ together is optionallysubstituted by 1 substituent.In one aspect the group formed by R² and R³ together is optionallysubstituted by 2 substituents.In one aspect the group formed by R² and R³ together is optionallysubstituted by 3 substituents.In one aspect A is optionally substituted by 0 substituents.In one aspect A is optionally substituted by 1 substituent.In one aspect A is optionally substituted by 2 substituents.In one aspect A is optionally substituted by 3 substituents.In one aspect the phenyl and heteroaryl groups in R⁶ and R⁷ areindependently optionally substituted by 0 substituents.In one aspect the phenyl and heteroaryl groups in R⁶ and R⁷ areindependently optionally substituted by 1 substituent.In one aspect the phenyl and heteroaryl groups in R⁶ and R⁷ areindependently are optionally substituted by 2 substituents.In one aspect the phenyl and heteroaryl groups in R⁶ and R⁷ areindependently are optionally substituted by 3 substituents.In one aspect of the invention Q is a direct bond and X is a directbond.

Particular classes of compounds of the present invention are disclosedin Table A using combinations of the definitions described hereinabove.For example, ‘a’ in the column headed R² in the table refers todefinition (a) given for R² hereinabove and ‘I’ refers to the firstdefinition given for the variables in the compound of formula (I) at thebeginning of the description. R⁶ and R⁷ are optional substituents on R²and the group formed by R² and R³ together. R² and R³ may of course beunsubstituted or substituted by the values listed for R⁶ and R⁷. A “-”in the column for R⁶ and R⁷ means that the relevant R² group or thegroup formed by R² and R³ together is unsubstituted. Table A refers tocompounds of the formula (1).

TABLE A R² and R³ Class Q R¹ R² R⁶ R³ together R⁷ X Y A 1 I I a I I — —I I I 2 I a — — — I I I I I 3 I b a I I — — a a a 4 a I — — — I I a a a5 c I a I I — — a a a 6 b c — — — a g d c a 7 b d b g b — — d c b 8 b ec g b — — d c a 9 b f d — c — — d c e 10 b h d — c — — d c e

Particular classes of compounds of the formula (1a) are disclosed inTable B using combinations of the definitions described hereinabove in asimilar manner as for Table A.

TABLE B R² and R³ Class R¹ R² R⁶ R³ together R⁷ 1a I I I I — — 2a a — —— I I 3a b a I I — — 4a I — — — I I 5a I a I I — — 6a c — — — a g 7a d bg b — — 8a e c g c — — 9a f d — — — — 10a  h d — — — —

Particular classes of compounds of the formula (1b) are disclosed inTable B using combinations of the definitions described hereinabove in asimilar manner as for Table A.

TABLE C R² and R³ Class R¹ R² R⁶ R³ together R⁷ 1b I I I I — — 2b a — —— I I 3b b a I I — — 4b I — — — I I 5b I a I I — — 6b c — — — a g 7b d bg b — — 8b e c g c — — 9b f d — — — — 10b  h d — — — —

A further class of compounds is of formula (1) wherein:

Q is a single bond;R¹ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, heterocyclyl,arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₃₋₇cycloalkylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl or C₃₋₇cycloalkylC₂₋₃alkynyl, [each of whichis optionally substituted by 1, 2 or 3 substituents independentlyselected from C₁₋₃alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl,C₁₋₃alkoxy, C₁₋₃alkylS(O)_(n)— (wherein n is 0, 1, 2 or 3),R⁵CON(R^(5′))—, (R^(5′))(R⁵″)NC(O)—, R^(5′)C(O)O—, R^(5′)OC(O)—,(R^(5′))(R^(5″))NC(O)N(R^(5′″))—, R⁵SO₂N(R^(5″))—, and(R^(5′))(R⁵″)NSO₂— (wherein R⁵ is C₁₋₃alkyl optionally substituted by 1,2 or 3 substituents selected from to hydroxyl, halo or cyano; andR^(5′) and R^(5″) are independently selected from hydrogen and C₁₋₃alkyloptionally substituted by 1, 2 or 3 substituents independently selectedfrom hydroxyl, halo, C₁₋₃alkoxy, carboxy and cyano or R^(5′) and R^(5″)together with the nitrogen atom to which they are attached form a 4-7membered saturated ring)];R² is selected from heterocyclyl, C₃₋₇cycloalkyl(CH₂)_(m)—, andC₆₋₁₂polycycloalkyl(CH₂)_(m)— (wherein m is 0, 1 or 2 and the rings areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R⁶);R³ is selected from hydrogen, C₁₋₄alkyl C₃₋₅cycloalkyl andC₃₋₄cycloalkylmethyl (each of which is optionally substituted by 1, 2 or3 fluoro atoms);R² and R³ together with the nitrogen atom to which they are attachedform a saturated mono, bicyclic or bridged ring system optionallycontaining 1 or 2 additional ring heteroatoms selected from nitrogen,oxygen and sulphur and which is optionally fused to a saturated,partially saturated or unsaturated monocyclic ring wherein the resultingring system is optionally substituted by 1, 2, or 3 substituentsindependently selected from R⁷;R⁶ and R⁷ are independently selected from hydroxyl, halo, oxo, carboxy,cyano, trifluoromethyl, R⁹, R⁹O—, R⁹CO—, R⁹C(O)O—, R⁹CON(R^(9′))—,(R^(9′))(R⁹″)NC(O)—, (R^(9′))(R⁹″)N—, R⁹S(O)_(a)— wherein a is 0 to 2,R^(9′)OC(O)—, (R^(9′))(R⁹″)NSO₂—, R⁹SO₂N(R^(9″))—,(R^(9′))(R^(9″))NC(O)N(R^(9′″))—, phenyl and heteroaryl [wherein thephenyl and heteroaryl groups are optionally fused to a phenyl,heteroaryl or a saturated or partially-saturated 5- or 6-membered ringoptionally containing 1, 2 or 3 heteroatoms independently selected fromnitrogen, oxygen and sulphur and the resulting ring system is optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₄alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino,di-N,N—(C₁₋₄alkyl)amino, N—C₁₋₄alkylcarbamoyl,di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(r)—,C₁₋₄alkylS(O)_(r)C₁₋₄alkyl (wherein r is 0, 1 or 2)];R⁹ is independently selected from C₁₋₃alkyl optionally substituted byhydroxyl, halo, C₁₋₄alkoxy, carboxy or cyano;R^(9′), R^(9″) and R^(9′″) are independently selected from hydrogen andC₁₋₃alkyl optionally substituted by 1, 2, or 3 substituentsindependently selected from hydroxyl, halo, C₁₋₄alkoxy, carboxy andcyano);

A is a phenyl or heteroaryl ring (the phenyl or heteroaryl ring beingoptionally substituted on ring carbon atoms by 1, 2 or 3 R¹⁰ groups andon an available ring nitrogen in a heteroaryl group by R¹¹);

R¹⁰ is independently selected from C₁₋₄alkyl, hydroxyl, cyano,trifluoromethyl, trifluoromethoxy, halo, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino, di-N,N—(C₁₋₄alkyl)amino,N—C₁₋₄alkylcarbamoyl, di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(s)—,C₁₋₄alkylS(O)_(s)C₁₋₄alkyl (wherein s is 0, 1 or 2)];R¹¹ is independently C₁₋₃alkyl optionally substituted by 1, 2 or 3fluoro atoms;X is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹²)(R¹³)—, —C(R¹²)(R¹³)C(R¹⁴)(R¹⁵)—, —CH₂O— or —CH₂S(O)_(t)—(wherein t is 0, 1 or 2):Y is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹⁶)(R¹⁷)— or —C(R¹⁸)(R¹⁹)C(R²⁰)(R²¹)—;wherein R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ areindependently selected from hydrogen and methyl;

or a pharmaceutically-acceptable salt thereof.

Yet a further class of compound is of formula (1) wherein:

Q is a single bond;R¹ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, heterocyclyl,arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₃₋₇cycloalkylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl or C₃₋₇cycloalkylC₂₋₃alkynyl, [each of whichis optionally substituted by 1, 2 or 3 substituents independentlyselected from C₁₋₃alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl,C₁₋₃alkoxy, C₁₋₃alkylS(O)_(n)— (wherein n is 0, 1, 2 or 3),R⁵CON(R^(5′))—, (R^(5′))(R^(5″))NC(O)—, R^(5′)C(O)O—, R^(5′)OC(O)—,(R^(5′))(R^(5″))NC(O)N(R^(5′″))—, R⁵SO₂N(R^(5″))—, and(R^(5′))(R⁵″)NSO₂— (wherein R⁵ is C₁₋₃alkyl optionally substituted by 1,2 or 3 substituents selected from hydroxyl, halo or cyano; andR^(5′) and R^(5″) are independently selected from hydrogen and C₁₋₃alkyloptionally substituted by 1, 2 or 3 substituents independently selectedfrom hydroxyl, halo, C₁₋₃alkoxy, carboxy and cyano or R^(5′) and R^(5″)together with the nitrogen atom to which they are attached form a 4-7membered saturated ring)];R² is selected from heterocyclyl, C₃₋₇cycloalkyl(CH₂)_(m)—, andC₆₋₁₂polycycloalkyl(CH₂)_(m)— (wherein m is 0, 1 or 2 and the rings areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R⁶);R³ is selected from hydrogen, C₁₋₄alkyl C₃₋₅cycloalkyl andC₃₋₅cycloalkylmethyl (each of which is optionally substituted by 1, 2 or3 fluoro atoms);R² and R³ together with the nitrogen atom to which they are attachedform a saturated mono, bicyclic or bridged ring system optionallycontaining 1 or 2 additional ring heteroatoms selected from nitrogen,oxygen and sulphur and which is optionally fused to a saturated,partially saturated or unsaturated monocyclic ring wherein the resultingring system is optionally substituted by 1, 2, or 3 substituentsindependently selected from R⁷;R⁶ and R⁷ are independently selected from hydroxyl, halo, oxo, carboxy,cyano, trifluoromethyl, R⁹, R⁹O—, R⁹CO—, R⁹C(O)O—, R⁹CON(R^(9′))—,(R^(9′))(R⁹″)NC(O)—, (R^(9′))(R⁹″)N—, R⁹S(O)_(a)— wherein a is 0 to 2,R^(9′)OC(O)—, (R^(9′))(R⁹″)NSO₂—, R⁹SO₂N(R^(9″))—,(R^(9′))(R^(9″))NC(O)N(R^(9′″))—, phenyl and heteroaryl [wherein thephenyl and heteroaryl groups are optionally fused to a phenyl,heteroaryl or a saturated or partially-saturated 5- or 6-membered ringoptionally containing 1, 2 or 3 heteroatoms independently selected fromnitrogen, oxygen and sulphur and the resulting ring system is optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₄alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino,di-N,N—(C₁₋₄alkyl)amino, N—C₁₋₄alkylcarbamoyl,di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(r)—,C₁₋₄alkylS(O)_(r)C₁₋₄alkyl (wherein r is 0, 1 or 2)];R⁹ is independently selected from C₁₋₃alkyl optionally substituted byhydroxyl, halo, C₁₋₄alkoxy, carboxy or cyano;R^(9′), R^(9″) and R^(9′″) are independently selected from hydrogen andC₁₋₃alkyl optionally substituted by 1, 2, or 3 substituentsindependently selected from hydroxyl, halo, C₁₋₄alkoxy, carboxy andcyano);

A is a phenyl or heteroaryl ring (the phenyl or heteroaryl ring beingoptionally substituted on ring carbon atoms by 1, 2 or 3 R¹⁰ groups andon an available ring nitrogen in a heteroaryl group by R¹¹);

R¹⁰ is independently selected from C₁₋₄alkyl, hydroxyl, cyano,trifluoromethyl, trifluoromethoxy, halo, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino, di-N,N—(C₁₋₄alkyl)amino,N—C₁₋₄alkylcarbamoyl, di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(s)—,C₁₋₄alkylS(O)_(s) C₁₋₄alkyl (wherein s is 0, 1 or 2)];R¹¹ is independently C₁₋₃alkyl optionally substituted by 1, 2 or 3fluoro atoms; either X is a direct bond andY is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹⁶)(R¹⁷)— or —C(R¹⁸)(R¹⁹)C(R²⁰)(R²¹)—; orX is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹²)(R¹³)—, —C(R¹²)(R¹³)C(R¹⁴)(R¹⁵)—, —CH₂O— or —CH₂S(O)_(t)—(wherein t is 0, 1 or 2) andY is a direct bond;wherein R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ areindependently selected from hydrogen and methyl;

or a pharmaceutically-acceptable salt thereof.

Yet a further class of compound is of formula (1) wherein:

Q is a single bond;R¹ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, heterocyclyl,arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₃₋₇cycloalkylC₁₋₃alkyl,C₃₋₇cycloalkylC₂₋₃alkenyl or C₃₋₇cycloalkylC₂₋₃alkynyl, [each of whichis optionally substituted by 1, 2 or 3 substituents independentlyselected from C₁₋₃alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl,C₁₋₃alkoxy, C₁₋₃alkylS(O)_(n)— (wherein n is 0, 1, 2 or 3),R⁵CON(R^(5′))—, (R^(5′))(R⁵″)NC(O)—, R^(5′)C(O)O—, R^(5′)OC(O)—,(R^(5′))(R^(5″))NC(O)N(R^(5′″))—, R⁵SO₂N(R^(5″))—, and(R^(5′))(R⁵″)NSO₂— (wherein R⁵ is C₁₋₃alkyl optionally substituted by 1,2 or 3 substituents selected from hydroxyl, halo or cyano; andR^(5′) and R^(5″) are independently selected from hydrogen and C₁₋₃alkyloptionally substituted by 1, 2 or 3 substituents independently selectedfrom hydroxyl, halo, C₁₋₃alkoxy, carboxy and cyano or R^(5′) and R^(5″)together with the nitrogen atom to which they are attached form a 4-7membered saturated ring)];R² is selected from heterocyclyl, C₃₋₇cycloalkyl(CH₂)_(m)—, andC₆₋₁₂polycycloalkyl(CH₂)_(m)— (wherein m is 0, 1 or 2 and the rings areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R⁶);R³ is selected from hydrogen, C₁₋₄alkyl C₃₋₅cycloalkyl andC₃₋₅cycloalkylmethyl (each of which is optionally substituted by 1, 2 or3 fluoro atoms);R² and R³ together with the nitrogen atom to which they are attachedform a saturated mono, bicyclic or bridged ring system optionallycontaining 1 or 2 additional ring heteroatoms selected from nitrogen,oxygen and sulphur and which is optionally fused to a saturated,partially saturated or unsaturated monocyclic ring wherein the resultingring system is optionally substituted by 1, 2, or 3 substituentsindependently selected from R⁷;R⁶ and R⁷ are independently selected from hydroxyl, halo, oxo, carboxy,cyano, trifluoromethyl, R⁹, R⁹O—, R⁹CO—, R⁹C(O)O—, R⁹CON(R^(9′))—,(R^(9′))(R⁹″)NC(O)—, (R^(9′))(R⁹″)N—, R⁹S(O)_(a)— wherein a is 0 to 2,R^(9′)OC(O)—, (R^(9′))(R⁹″)NSO₂—, R⁹SO₂N(R^(9″))—,(R^(9′))(R^(9″))NC(O)N(R^(9′″))—, phenyl and heteroaryl [wherein thephenyl and heteroaryl groups are optionally fused to a phenyl,heteroaryl or a saturated or partially-saturated 5- or 6-membered ringoptionally containing 1, 2 or 3 heteroatoms independently selected fromnitrogen, oxygen and sulphur and the resulting ring system is optionallysubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₄alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino,di-N,N—(C₁₋₄alkyl)amino, N—C₁₋₄alkylcarbamoyl,di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(r)—,C₁₋₄alkylS(O)_(r)C₁₋₄alkyl (wherein r is 0, 1 or 2)];R⁹ is independently selected from C₁₋₃alkyl optionally substituted byhydroxyl, halo, C₁₋₄alkoxy, carboxy or cyano;R^(9′), R^(9″) and R^(9′″) are independently selected from hydrogen andC₁₋₃alkyl optionally substituted by 1, 2, or 3 substituentsindependently selected from hydroxyl, halo, C₁₋₄alkoxy, carboxy andcyano);A is a phenyl or heteroaryl ring (the phenyl or heteroaryl ring beingoptionally substituted on ring carbon atoms by 1, 2 or 3 R¹⁰ groups andon an available ring nitrogen in a heteroaryl group by R¹¹);R¹⁰ is independently selected from C₁₋₄alkyl, hydroxyl, cyano,trifluoromethyl, trifluoromethoxy, halo, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino, di-N,N—(C₁₋₄alkyl)amino,N—C₁₋₄alkylcarbamoyl, di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(s)—,C₁₋₄alkylS(O)_(s)C₁₋₄alkyl (wherein s is 0, 1 or 2)];R¹¹ is independently C₁₋₃alkyl optionally substituted by 1, 2 or 3fluoro atoms;X is a direct bond;Y is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹⁶)(R¹⁷)— or

—C(R¹⁸)(R¹⁹)C(R²⁰)(R²¹)—; or

X is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹²)(R¹³)—, —C(R¹²)(R¹³)C(R¹⁴)(R¹⁵)—, —CH₂O— or —CH₂S(O)_(t)—(wherein t is 0, 1 or 2) andY is a direct bond;wherein R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ areindependently selected from hydrogen and methyl;

or a pharmaceutically-acceptable salt thereof.

In another aspect of the invention, suitable compounds of the inventionare any one or more of the Examples or a pharmaceutically-acceptablesalt thereof.

In another aspect of the invention, suitable compounds of the inventionare any one or more of the following or a pharmaceutically-acceptablesalt thereof:

-   4-[4-[[(1S,3R)-5-hydroxy-2-adamantyl]carbamoyl]-5-propylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[4-(1-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[4-(N-cyclohexyl-N-methyl-carbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[4-(oxan-4-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[5-propylsulfanyl-4-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl]pyrazol-1-yl]benzoic    acid;-   4-[4-(cyclohexylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid;-   4-[4-(2-adamantylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid;-   4-[4-(1-adamantylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid;-   4-[4-(cyclohexyl-methyl-carbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic    acid;-   4-[5-cyclopropyl-4-[(4-hydroxy-1-adamantyl)carbamoyl]pyrazol-1-yl]benzoic    acid;-   2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetic    acid;-   2-[4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetic    acid;-   4-(4-cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoic    acid;-   3-(4-cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoic    acid;-   3-[4-(adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-ylmethyl]-benzoic    acid;-   4-[4-(adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-ylmethyl]-benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid;-   4-[4-(2-adamantylcarbamoyl)-5-(1-methylcyclopropyl)pyrazol-1-yl]benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoic acid;-   4-[4-(2-adamantylcarbamoyl)-5-ethylpyrazol-1-yl]benzoic acid;-   4-[4-(2-adamantylcarbamoyl)-5-propan-2-ylpyrazol-1-yl]benzoic acid;-   4-[4-(2-adamantylcarbamoyl)-5-cyclobutylpyrazol-1-yl]benzoic acid;-   4-[4-(2-adamantylcarbamoyl)-5-methyl-pyrazol-1-yl]benzoic acid;-   4-(5-tert-butyl-4-(cyclohexylcarbamoyl)-1H-pyrazol-1-yl)benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[4-(1-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[5-cyclohexylsulfanyl-4-[(5-hydroxy-2-adamantyl)carbamoyl]pyrazol-1-yl]benzoic    acid;-   4-[5-cyclohexylsulfanyl-4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]pyrazol-1-yl]benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoic    acid;-   methyl    4-[4-(1-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate;-   methyl    4-[5-cyclopentylsulfanyl-4-[[(1R,3S)-5-hydroxy-2-adamantyl]carbamoyl]pyrazol-1-yl]benzoate;-   4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoic    acid;-   4-[4-(cyclohexylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[5-cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-methylsulfanyl-pyrazol-1-yl]benzoic    acid;-   4-[4-(5-methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-2-methoxy-benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoic    acid;-   4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoic    acid; or-   4-[4-(adamantan-2-ylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzoic    acid.

Another aspect of the present invention provides a process for preparinga compound of formula (1) or a pharmaceutically acceptable salt thereofwhich process (wherein variable groups are, unless otherwise specified,as defined in formula (1)) comprises any one of processes a) or b):

a) hydrolysis of an ester of formula (2):

wherein R²² is an alkyl or aryl group; orb) converting Z in a compound of the formula (3):

into a carboxy group, wherein Z is an functional group capable ofconversion into a carboxylic acid;and thereafter if necessary or desirable:i) converting a compound of the formula (1) into another compound of theformula (1);ii) removing any protecting groups;iii) resolving enantiomers;iv) forming a pharmaceutically-acceptable salt thereof.

Examples of conversions of a compound of Formula (1) into anothercompound of Formula (1), well known to those skilled in the art, includefunctional group interconversions such as hydrolysis, hydrogenation,hydrogenolysis, oxidation or reduction, and/or further functionalisationby standard reactions such as amide or metal-catalysed coupling, ornucleophilic displacement reactions.

Suitable conditions for the above processes a) to b) are as follows.

Process a) may be carried out under either acidic or basic conditionsdependant on the nature of the ester group (R²²) but typically may becarried out under basic conditions, for example with aqueous sodiumhydroxide, using a suitable solvent such as methanol for example.Typically the reaction is carried out at ambient temperature, howeversome esters may require cleavage using Microwave or conventionalheating, for example at temperatures between 30-100° C. Examples ofsuitable values for R²² include methyl, ethyl, tert-butyl, phenyl,benzyl and paramethoxybenzyl, particularly methyl or ethyl.

Compounds of formula (2) may be made by processes known in the art andtypically by reaction of a compound of Formula (4) with a compound ofFormula (5):

Such reactions may be carried out by direct treatment of esters withamines or alternatively by hydrolysis of the R²³ ester group to anintermediate carboxylic acid followed by conventional amide couplingreactions. Methods and standard conditions for orthogonal removal ofester groups are known persons skilled in the art, for example if R²² isethyl and R²³ is tert-butyl, R²³ may be selectively cleaved under acidicconditions.

Amide formation can be carried out in a suitable solvent such asdichloromethane for example with the addition of a suitable couplingagent (or combination of agents) such as to HOBT and EDCI for example,optionally in the presence of a suitable base such as triethylamine orN,N-di-iso-propylamine for example. Typically the reaction is carriedout at ambient or elevated temperature between 0-60° C.

Compounds of formula (4) in which Q is a sulphur, oxygen or nitrogenatom may be made by processes known in the art and typically by reactionof a compound of Formula (6) with displacement of an appropriate leavinggroup (L):

wherein L is a suitable leaving group, for example halo or triflate (inparticular fluoro or chloro), R²² is an alkyl or aryl group and R²⁴ iseither —OR²³ or NR²R³.

Displacements may be carried out for example using a suitablenucleophilic reagent, for example propane thiol, in a suitable solventsuch as DMF for example in the presence of an appropriate base, forexample sodium hexamethyldisilazide (NaHMDS). Typically the reaction iscarried out at ambient temperature when L is chloro, however somereactions may require using Microwave or conventional heating, forexample at temperatures between 30-100° C.

Compounds of formula (6) may be made by processes known in the art andtypically by functional group interconversion of a compound of Formula(7).

wherein R²² is an alkyl or aryl group and R²⁴ is either —OR²³ or NR²R³.

Examples of such processes are known to the art and may be carried outusing a combination of reagents such as tert-butylnitrite with a cuprichalide in a suitable solvent such as acetonitrile for example. Typicallythe reaction is carried out at elevated temperature when for example, Lis chloro, using Microwave or conventional heating, for example attemperatures between 60-100° C.

Compounds of formula (7) may be made by processes known in the art andtypically by reaction of a hydrazine of formula (8) with an enol etherof Formula (9).

wherein R²² is an alkyl or aryl group, R²⁴ is either —OR²³ or NR²R³ andR²⁵ is an alkyl group. In particular, R²⁵ is methyl or ethyl.

Examples of such processes are known to the art and are typicallycarried out using a in a suitable solvent such as ethanol for example inthe presence of a suitable base such as DIPEA for example. Typically thereaction is carried out at elevated temperature using Microwave orconventional heating, for example at temperatures between 60-100° C.Hydrazines of formula (8) are known in the chemical literature or may beprepared using standard conditions known to those skilled in the art.

Compounds of formula (9) may be made by processes known in the art andtypically by functionalisation of a ketonitrile of Formula (10).

wherein R²⁴ is either —OR23 or NR²R³.

Examples of such processes are known to the art and are typicallycarried out using a combination of reagents, for example neat aceticanhydride and triethyl orthoformate. Typically the reaction is carriedout at elevated temperature using Microwave or conventional heating, forexample at temperatures between 60-100° C. Ketonitriles of formula (10)are known in the chemical literature or may be prepared using standardconditions known to those skilled in the art.

Compounds of formula (4) in which Q is a single bond may also beprepared by processes known in the art and typically involve theformation of a functionalised keto ester of Formula (11B) wherein Xrepresents either dialkylamino (such as dimethylamino) or lower alkoxy(such as methoxy or ethoxy) and subsequent reaction with hydrazines ofFormula (8)

The ketoesters of formula (11B) are known in the chemical literature ormay be prepared using standard conditions known to those skilled in theart, including by reaction of an acid chloride with Meldrum's acid (seefor example J. Org. Chem. 2001, 26, 6756) in an inert solvent such asdichloromethane in the presence of a base such as pyridine, followed byreaction of the resultant intermediate with an alcohol HOR²³ (see forexample J. Org. Chem. 1978, 43, 2087)

Compounds of formula (2) in which Q is a single bond may also beprepared by processes known in the art and typically involve theformation of a functionalised keto amide of Formula (12) wherein X′represents either dialkylamino (such as dimethylamino) or lower alkoxy(such as methoxy or ethoxy) and subsequent reaction with hydrazines ofFormula (8)

Ketoamides of formula (13) are known in the chemical literature or maybe prepared using standard conditions known to those skilled in the art,including by reaction of an amine with a suitable acid chloride,optionally prepared in situ from the corresponding acid, or by reactionof an enolate anion, generated by treating a ketone with a strong base(such as LDA), with an appropriate isocyanate.

An example of process b) is the conversion of an aryl halide into anaryl carboxylic acid through the use of metal-catalysed carbonylation.Examples of such processes are known to the art and are carried out in asuitable solvent such as ethanol/dioxane for example using a suitablecatalyst, or combination of catalysts, for example, Herrmann's catalysttogether with Fu's salt in the presence of a suitable source of carbonmonoxide, for example, molybdenum hexacarbonyl or gaseous CO typicallyin the presence of a suitable base, or combination of bases for exampleDMAP/DIPEA. Typically the reaction is carried out at elevatedtemperature using Microwave or conventional heating, for example attemperatures between 100-180° C. It will be appreciated by those skilledin the art that the choice of solvent will depend on the nature of theproduct isolated, for example alcoholic solvents will tend to lead toisolation of the ester which may be subsequently cleaved on is work-upof the reaction to give the appropriate acid. It will also beappreciated by those skilled in the art that compounds of formula (3)may be accessed by all of the methods used to describe the synthesis ofcompounds of formula (2).

In addition, a compound of formula (3) may be prepared:

by reaction of a suitably functionalised moiety of formula (3A) with anN unsubstituted pyrazole of formula (3B) to provide the precursor offormula (3)

wherein L′ is a leaving group capable of being displaced in an SN2reaction (when Y becomes joined by an sp3 carbon to the ring) or in SNArreaction (when Y becomes joined by an sp2 carbon to the ring; optionallycatalysed by appropriate transition metal catalysts, for exampleBuchwald displacements) and in which optionally involves deprotonationof the pyrazole (3B) by a base such as potassium t-butoxide. L′ is aleaving group such as chloro, bromo or iodo.

The reactions described above may be performed under standard conditionsknown to the person skilled in the art. The intermediates describedabove are commercially available, are known in the art or may beprepared by known procedures and/or by the procedures shown above.

It will be appreciated that certain of the various substituents in thecompounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for example hydroxylamine, orwith hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present inventionpossess 11βHSD1 inhibitory activity. These properties may be assessedusing the following assay.

Assays

The conversion of cortisone to the active steroid cortisol by 11βHSD1oxo-reductase activity, can be measured using a competitive homogeneoustime resolved fluorescence assay (HTRF) (CisBio International, R&D,Administration and Europe Office, In Vitro Technologies—HTRF®/BioassaysBP 84175, 30204 Bagnols/Cèze Cedex, France. Cortisol bulk HTRF kit: CatNo. 62CORPEC).

The evaluation of compounds described herein was carried out using abaculovirus expressed N terminal 6-His tagged full length human 11βHSD1enzyme(*1). The enzyme was purified from a detergent solubilised celllysate, using a copper chelate column. Inhibitors of 11βHSD1 reduce theconversion of cortisone to cortisol, which is identified by an increasein signal, in the above assay. *1 The Journal of Biological Chemistry,Vol. 26, No 25, pp 16653-16658

Compounds to be tested were dissolved in dimethyl sulphoxide (DMSO) to10 mM and diluted further in assay buffer containing 1% DMSO to 10 foldthe final assay concentration. Diluted compounds were then plated intoblack 384 well plates (Matrix, Hudson N.H., USA).

The assay was carried out in a total volume of 20 μl consisting ofcortisone (Sigma, Poole, Dorset, UK, 160 nM), glucose-6-phosphate (RocheDiagnostics, 1 mM), NADPH (Sigma, Poole, Dorset, 100 μM),glucose-6-phosphate dehydrogenase (Roche Diagnostics, 12.5 μg/ml), EDTA(Sigma, Poole, Dorset, UK, 1 mM), assay buffer (K₂HPO₄/KH₂PO₄, 100 mM)pH 7.5, recombinant 11βHSD1 [using an appropriate dilution to give aviable assay window—an example of a suitable dilution may be 1 in 1000dilution of stock enzyme] plus test compound. The assay plates wereincubated for 25 minutes at 37° C. after which time the reaction wasstopped by the addition of 10 μl of 0.5 mM glycerrhetinic acid plusconjugated cortisol (XL665 or D2). 10 μl of anti-cortisol Cryptate wasthen added and the plates sealed and incubated for 6 hours at roomtemperature. Fluorescence at 665 nm and 620 nm was measured and the 665nm:620 nm ratio calculated using an Envision plate reader.

These data were then used to calculate IC₅₀ values for each compound(Origin 7.5, Microcal software, Northampton Mass., USA) and/or the %inhibition at 30 μM of compound.

Compounds of the present invention typically show an IC₅₀ of less than30 μM, and preferably less than 5 μM.

For example, the following results were obtained:

IC50 Ex. No. (uM) 3 0.012 6 3.505 4 0.034 8 0.161 17 0.004 20 0.006 220.008 23 0.004 24 0.005 27 0.008 33 0.009 36 0.004 38 0.007 41 0.003 430.185 44 0.005The following table displays % inhibition of human 11-βHSD at a testconcentration of 30 μM of compound

% Ex. No. @30 uM 1 91 2 93 3 105 4 114 5 90 6 80 7 91 8 94 9 78 10 84 1182 12 92 13 96 14 89 15 92 16 91 17 95 18 89 19 90 20 90 21 91 22 98 23102 24 104 25 90 26 100 27 95 28 87 29 91 30 91 31 105 32 103 33 97 34100 35 94 36 89 37 94 38 91 39 98 40 99 41 91 42 94 43 97 44 94 45 94 4698 47 90

The oral bioavailability of the compounds of the invention may be testedas follows:

Determination of Bioavailability in PK Studies

Compounds are dosed intravenously at 2 mg/kg (2 ml/kg) and orally at 5mg/kg (5 ml/kg) in a 25% HPBCD in sorrensons buffer pH 5.5 formulation.Blood samples (200 ul) are taken Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8and 24 h post dose for both routes and plasma prepared bycentrifugation. Plasma samples are analysed as below. PK parameters(clearance, volume of distribution, bioavailability, fraction absorbedetc.) are calculated by standard PK methods using suitable PK software(WinNon-Lin).

Bioanalysis of Plasma Samples

The guidelines described are for the manual preparation of plasmasamples following single compound or cassette dosing of projectcompounds to all PK species used within discovery DMPK. Analysis by openaccess (LC-MS/MS) or manual approaches (LC-MS) is described.

Contents

1. Materials

2. Generic Extraction Method

3. Example Sample List Using Generic Plate Layout

4. Open Access Batch Submission and System Checks

5. Acceptance Criteria for Batch Pass

1. Materials

Solvents: Methanol, acetonitrile and DMSOWater: Purified or HPLC grade1 ml shallow 96-well plates OR eppendorf tubes2 ml deep well 96-well plates plus lidsBlank (control) plasma

2. Generic Extraction Method

Solubilise compound(s) to 1 mg/ml using DMSO taking into account saltfactors if any. The DMSO stock(s) may be used to make all calibration &quality control (QC) samples:

2.i Single Compound Analysis 2.i.a Preparation of Calibration and QCSamples:

-   -   1. Prepare standard solutions as follows:

Stock Volume Volume Post plasma diluted methanol stock Standard dilutionconc. ng/ml ml ml conc. ng/ml ng/ml 1 mg/ml 0.9 0.1 100,000 10,000100,000 0.5 0.5 50,000 5,000 50,000 0.75 0.5 20,000 2,000 20,000 0.5 0.510,000 1,000 10,000 0.5 0.5 5,000 500 5,000 2 0.5 1,000 100 1,000 0.50.5 500 50 500 0.75 0.5 200 20 200 0.5 0.5 100 10 100 0.5 0.5 50 5 500.5 0.5 10 1

-   -   2. Transfer 50 ul blank plasma to a well of a 1 ml 96-well plate        (shallow well)    -   3. Transfer 5 ul of each of the standard solutions to further        wells of the plate    -   4. Add 50 ul blank plasma to each of these wells.    -   5. To generate the QC samples, add three aliquots of 5 ul of the        100 ng/ml, 1000 ng/ml and 10,000 ng/ml standard solutions to the        plate (3 QCs at each concentration).    -   6. Add 50 ul blank plasma to each of these.    -   7. Transfer 50 ul of each PK sample to the 1 ml 96-well plate    -   8. Add 5 ul methanol (− compound) to each of the PK samples    -   9. Ensure all dose formulations are well mixed by vortex mixing.    -   10. Dilute intravenous (IV) and oral dose (PO) formulations of        expected concentration to 10 ug/ml in methanol. (For example, a        formulation made to an expected concentration of 2 mg/ml would        be diluted 1:200 to give 10 ug/ml solution).    -   11. Add 6×50 ul aliquots of plasma to the plate. Add 5 ul of        diluted IV formulation to three of the wells, repeat with PO        formulation and remaining 3 wells.    -   12. Precipitate proteins by adding 100 ul acetonitrile        containing a project related internal standard (at 1 ug/ml) to        all calibration, QC, PK and formulation samples.    -   13. Vortex mix the plate before centrifugation at 4,000 g for 10        minutes.    -   14. Transfer 100 ul of the supernatant to the wells of a 2 ml        96-well plate (see following plate map). Care should be taken        not to disturb the pellet.    -   15. Add ˜1.5 ml of 50:50 Methanol:Water into the last well.    -   16. For analysis on triple quad systems: add 400 ul water (HPLC        grade) to each sample. Gently mix.    -   17. Add 100 ul of the 100,000 ng/ml stock of each of the        standard solutions to the 2 ml plate and add 900 ul water. Add a        sample of internal standard to a further well (see plate map).        These are for compound tuning (denoted on the plate map as tune        solutions)    -   18. For analysis on platform systems: add 100 ul water (HPLC        grade) to each sample. Gently mix.    -   19. Manually tune all compounds using compound solutions        prepared to 5,000 ng/ml (add 100 ul of the 50,000 ng/ml standard        solutions to 900 ul water)

2.ii Cassette Dose Analysis 2.iia Preparation of Calibration and QCSamples:

Note: For cassette dosing, the amount of methanol required to dilute the1 mg/ml stock will be adjusted according to the number of compoundspresent.

-   -   1. Add 100 ul of each 1 mg/ml stock required to a vial.    -   2. Add the required volume of methanol to yield a total volume        of 1 ml.    -   3. Perform all further steps as for single compound analysis        (steps 2-16 above).        2.iii In Cases where PK Samples Exceed the Upper Limit of        Quantification (ULOQ).    -   1. Prepare a further calibration curve and QC samples as above        (steps 1-6).    -   2. Transfer <50 ul (e.g. 25 ul) of the PK samples that exceed        the ULOQ.    -   3. Add enough control plasma to these samples to yield a final        plasma volume of 50 ul. Make a note of the dilution made.    -   4. Transfer 50 ul of all remaining PK samples.    -   5. Prepare all formulation samples and extract all samples as        described above. (steps 8-16)        Note: Upper concentrations used to generate the calibration        curve may be reviewed, however, care must be taken to avoid        saturation of the HPLC column or MS equipment. It is for this        reason that dilution of PK samples is recommended.

2.iv In Cases of Poor Sensitivity (High Lower Limit of Quantification).

Note: High LLOQ is taken as when most of the plasma concentrations liebelow the lower limit of quantification or where the LLOQ is greater the10 ng/ml. The following methods should be applied when either of thesescenarios is encountered.

According to a further aspect of the invention there is provided apharmaceutical composition, which comprises a compound of the Examples,or a pharmaceutically-acceptable salt thereof, as defined hereinbeforein association with a pharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing). In general,compositions in a form suitable for oral use are preferred.

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

We have found that the compounds defined in the present invention, or apharmaceutically-acceptable salt thereof, are effective 11βHSD1inhibitors, and accordingly have value in the treatment of diseasestates associated with metabolic syndrome.

It is to be understood that where the term “metabolic syndrome” is usedherein, this relates to metabolic syndrome as defined in 1) and/or 2) orany other recognised definition of this syndrome. Synonyms for“metabolic syndrome” used in the art include Reaven's Syndrome, InsulinResistance Syndrome and Syndrome X. It is to be understood that wherethe term “metabolic syndrome” is used herein it also refers to Reaven'sSyndrome, Insulin Resistance Syndrome and Syndrome X.

According to a further aspect of the present invention there is provideda compound of formula (1), or a pharmaceutically-acceptable saltthereof, as defined hereinbefore for use in a method of prophylactic ortherapeutic treatment of a warm-blooded animal, such as man.

Thus according to this aspect of the invention there is provided acompound of formula (1), or a pharmaceutically-acceptable salt thereof,as defined hereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of formula (1), or a pharmaceutically-acceptable saltthereof, as defined hereinbefore in the manufacture of a medicament foruse in the production of an 11βHSD1 inhibitory effect in a warm-bloodedanimal, such as man.

Where production of or producing an 11βHSD1 inhibitory effect isreferred to suitably this refers to the treatment of metabolic syndrome.Alternatively, where production of an 11βHSD1 inhibitory effect isreferred to this refers to the treatment of diabetes, obesity,hyperlipidaemia, hyperglycaemia, hyperinsulinemia or hypertension,particularly diabetes and obesity. Alternatively, where production of an11βHSD1 inhibitory effect is referred to this refers to the treatment ofglaucoma, osteoporosis, tuberculosis, dementia, cognitive disorders ordepression.

Alternatively, where production of an 11βHSD1 inhibitory effect isreferred to this refers to the treatment of cognitive disorders, such asimproving the cognitive ability of an individual, for example byimprovement of verbal fluency, verbal memory or logical memory, or fortreatment of mild cognitive disorders. See for example WO03/086410 andreferences contained therein, and Proceedings of National Academy ofSciences (PNAS), to 2001, 98(8), 4717-4721.

Alternatively, where production of an 11βHSD1 inhibitory effect isreferred to this refers to the treatment of, delaying the onset ofand/or reducing the risk of atherosclerosis—see for example J.Experimental Medicine, 2005, 202(4), 517-527.

Alternatively, where production of an 11βHSD1 inhibitory effect isreferred to this refers to the treatment of Alzheimers and/orneurodegenerative disorders.

According to a further feature of this aspect of the invention there isprovided a method for producing an 11βHSD1 inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (1), or a pharmaceutically-acceptable salt thereof.

In addition to their use in therapeutic medicine, the compounds offormula (1), or a pharmaceutically-salt thereof, are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof 11βHSD1 in laboratory animals such as cats, dogs, rabbits, monkeys,rats and mice, as part of the search for new therapeutic agents.

The inhibition of 11βHSD1 described herein may be applied as a soletherapy or may involve, in addition to the subject of the presentinvention, one or more other substances and/or treatments. Such conjointtreatment may be achieved by way of the simultaneous, sequential orseparate administration of the individual components of the treatment.Simultaneous treatment may be in a single tablet or in separate tablets.For example agents than might be co-administered with 11βHSD1inhibitors, particularly those of the present invention, may include thefollowing main categories of treatment:

1) Insulin and insulin analogues;2) Insulin secretagogues including sulphonylureas (for exampleglibenclamide, glipizide), prandial glucose regulators (for examplerepaglinide, nateglinide), glucagon-like peptide 1 agonist (GLP1agonist) (for example exenatide, liraglutide) and dipeptidyl peptidaseIV inhibitors (DPP-IV inhibitors);3) Insulin sensitising agents including PPARγ agonists (for examplepioglitazone and rosiglitazone);4) Agents that suppress hepatic glucose output (for example metformin);5) Agents designed to reduce the absorption of glucose from theintestine (for example acarbose);6) Agents designed to treat the complications of prolongedhyperglycaemia; e.g. aldose reductase inhibitors7) Other anti-diabetic agents including phosphotyrosine phosphataseinhibitors, glucose 6-phosphatase inhibitors, glucagon receptorantagonists, glucokinase activators, glycogen phosphorylase inhibitors,fructose 1,6 bisphosphastase inhibitors, glutamine:fructose-6-phosphateamidotransferase inhibitors8) Anti-obesity agents (for example sibutramine and orlistat);9) Anti-dyslipidaemia agents such as, HMG-CoA reductase inhibitors(statins, eg pravastatin); PPARα agonists (fibrates, eg gemfibrozil);bile acid sequestrants (cholestyramine); cholesterol absorptioninhibitors (plant stanols, synthetic inhibitors); ileal bile acidabsorption inhibitors (IBATi), cholesterol ester transfer proteininhibitors and nicotinic acid and analogues (niacin and slow releaseformulations);10) Antihypertensive agents such as, β blockers (eg atenolol, inderal);ACE inhibitors (eg lisinopril); calcium antagonists (eg. nifedipine);angiotensin receptor antagonists (eg candesartan), α antagonists anddiuretic agents (eg. furosemide, benzthiazide);11) Haemostasis modulators such as, antithrombotics, activators offibrinolysis and antiplatelet agents; thrombin antagonists; factor Xainhibitors; factor VIIa inhibitors; antiplatelet agents (eg. aspirin,clopidogrel); anticoagulants (heparin and Low molecular weightanalogues, hirudin) and warfarin;12) Anti-inflammatory agents, such as non-steroidal anti-inflammatorydrugs (eg. aspirin) and steroidal anti-inflammatory agents (eg.cortisone); and13) Agents that prevent the reabsorption of glucose by the kidney (SGLTinhibitors).

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated by the following Examples inwhich, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18-25° C. and under an atmosphere of an inert gas such asargon;(ii) evaporation of solvent was carried out using a rotary evaporatorunder reduced pressure (600-4000 Pa; 4.5-30 mmHg) with a bathtemperature of up to 60° C.;(iii) chromatography means flash chromatography on silica gel;(iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;(v) yields are given for illustration only and are not necessarily thosewhich can be obtained by diligent process development; preparations wererepeated if more material was required;(vi) where given, NMR data (¹H) is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS), determined at 300 or 400 MHz (unless otherwisestated) using perdeuterio dimethyl sulfoxide (DMSO-d₆) as solvent,unless otherwise stated; peak multiplicities are shown thus: s, singlet;d, doublet; dd, doublet of doublets; dt, doublet of triplets; dm,doublet of multiplets; t, triplet, m, multiplet; br, broad;(vii) chemical symbols have their usual meanings; SI units and symbolsare used;(viii) solvent ratios are given in volume:volume (v/v) terms;(ix) mass spectra (MS) were run with an electron energy of 70 electronvolts in the chemical ionisation (CI) mode using a direct exposureprobe; where indicated ionisation was effected by electron impact (EI),fast atom bombardment (FAB) or electrospray (ESP); values for m/z aregiven; generally, only ions which indicate the parent mass are reported;(x) The following abbreviations may be used below or in the processsection hereinbefore:

-   -   Et₂O diethyl ether    -   DMF dimethylformamide    -   DCM dichloromethane    -   DME 1,2-dimethoxyethane    -   MeOH methanol    -   EtOH ethanol    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   DMSO dimethylsulfoxide    -   HOBT 1-hydroxybenzotriazole    -   EDCI (EDAC) 1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide        hydrochloride    -   DIPEA diisopropylethylamine    -   DMAP 4-dimethylaminopyridine    -   DEAD diethyl azodicarboxylate    -   EtOAc ethyl acetate    -   MgSO₄ magnesium sulfate    -   MTBE methyl tert-butyl ether    -   NaHMDS sodium hexamethyldisalazide

Example 14-[4-((1R,2S,3S,5S)-5-Hydroxy-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoicacid

4-[4-((1R,2S,3S,5S)-5-Hydroxy-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoicacid methyl ester (0.34 mmol) (Intermediate #1) was dissolved inmethanol (10 mL) and treated with 2M sodium hydroxide solution (0.84 mL,1.7 mmol). The mixture was stirred at ambient temperature for 24 h andthen the methanol was removed by evaporation under reduced pressure. Theresidue was dissolved in water (10 mL), acidified to pH4 with 2M HCl andextracted with EtOAc (2×10 mL). The combined extracts were washed withwater (10 mL) and brine (10 mL) and dried (MgSO₄) and evaporated toleave the title compound as a white solid. (74 mg, 48%).

¹H NMR (300.073 MHz, DMSO-d₆) δ0.66 (3H, t), 1.18-1.30 (2H, m), 1.42(2H, d), 1.58-1.80 (6H, m), 1.88 (2H, d), 2.06 (3H, s), 2.62 (2H, t),3.95-4.06 (1H, m), 4.42 (1H, s), 7.71 (2H, d), 7.95 (1H, d), 8.09 (2H,d), 8.16 (1H, s), 13.19 (1H, s)

MS m/z 456 M+H

Example 24-[4-(2-Adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid

Methyl4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (190mg, 0.42 mmol) (Intermediate #2) was dissolved in methanol (10 mL) andtreated at ambient temperature with 2M aqueous sodium hydroxide solution(1.05 mL, 2.1 mmol). The mixture was stirred at ambient temperature for18 h. and then heated to 65° C. for a further 2 h. Methanol was removedby evaporation under reduced pressure and the clear solution dilutedwith water (25 ml). 2M HCl was added to pH4 and the mixture extractedwith ethyl acetate (2×25 mL). The combined extracts were washed withwater (2×10 mL) and brine (10 mL), dried (MgSO₄) and evaporated to givethe title compound as a white solid. (174 mg, 94%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.65 (3H, t), 1.17-1.29 (2H, m), 1.60(2H, d), 1.73 (2H, s), 1.83 (6H, s), 1.91-2.05 (4H, m), 2.62 (2H, t),4.09 (1H, d), 7.75 (2H, d), 8.03 (1H, d), 8.13 (2H, d), 8.20 (1H, s)

MS m/z 440 M+H

Example 34-[4-(1-Adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid

Methyl4-[4-(1-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (143mg, 0.32 mmol) (Intermediate #3) was dissolved in methanol and treatedat ambient temperature with 2M aqueous sodium hydroxide solution. Themixture was stirred at ambient for 18 h. Methanol was removed byevaporation under reduced pressure and the clear solution diluted withwater (25 ml). 2M HCl was added to pH4 and the mixture extracted withethyl acetate (2×25 mL). The combined extracts were washed with water(2×10 mL) and brine (10 mL), dried (MgSO₄) and evaporated to give thetitle compound as a white solid (132 mg, 94%).

¹H NMR (300.073 MHz, DMSO-d₆) δ0.69 (3H, t), 1.25 (2H, q), 1.66 (6H, s),2.06 (9H, s), 2.65 (2H, t), 7.51 (1H, s), 7.66-7.69 (2H, m), 8.07-8.10(3H, m)

MS m/z 440 M+H

Example 44-[4-(N-Cyclohexyl-N-methyl-carbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoicacid

Methyl4-[4-(cyclohexyl-methyl-carbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate(Intermediate #4) (162 mg, 0.39 mmol) was dissolved in methanol (10 mL)and treated at ambient temperature with 2M aqueous sodium hydroxidesolution (0.96 mL, 1.95 mmol). The mixture was stirred at ambient for 18h. Methanol was removed by evaporation under reduced pressure and theclear solution diluted with water (25 ml). 2M HCl was added to pH4 andthe mixture extracted with ethyl acetate (2×25 mL). The combinedextracts were washed with water (2×10 mL) and brine (10 mL), dried(MgSO₄) and evaporated to give the title compound as a white solid foam(150 mg, 96%).

¹H NMR (300.073 MHz, DMSO-d₆) δ0.68 (3H, t), 1.10-1.41 (4H, m),1.42-1.85 (8H, m), 2.58 (2H, t), 2.86 (3H, s), 3.45-3.60 (0.5H, m),4.21-4.38 (0.5H, m), 7.74 (2H, d), 7.89 (1H, s), 8.09 (2H, d)

MS m/z 402 M+H

Example 54-[4-(Oxan-4-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid

Methyl 4-[4-(oxan-4-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate(Intermediate #5) (104 mg, 0.26 mmol) was dissolved in methanol (5 mL)and treated at ambient temperature with 2M aqueous sodium hydroxidesolution (0.65 mL, 1.29 mmol). The mixture was stirred at ambient for 18h. Methanol was removed by evaporation under reduced pressure and theclear solution diluted with water (25 ml). 2M HCl was added to pH4 andthe mixture extracted with ethyl acetate (2×25 mL). The combinedextracts were washed with water (2×10 mL) and brine (10 mL), dried(MgSO₄) and evaporated to give the product as a white solid (89 mg,85%).

¹H NMR (300.073 MHz, DMSO-d₆) δ0.68 (3H, t), 1.19-1.31 (2H, m),1.47-1.56 (2H, m), 1.77-1.81 (2H, m), 2.71 (2H, t), 3.29-3.43 (2H, m),3.85-3.89 (2H, m), 3.94-4.04 (1H, m), 7.67 (2H, d), 8.03 (1H, d), 8.09(2H, d), 8.16 (1H, s)

MS m/z 390 M+H

Example 64-[5-Propylsulfanyl-4-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl]pyrazol-1-yl]benzoicacid

Methyl4-[5-propylsulfanyl-4-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl]pyrazol-1-yl]benzoate(Intermediate #6) (177 mg, 0.34 mmol) was stirred at ambient temperaturefor 18 h in a mixture of methanol (5 mL) and 2M sodium hydroxide (0.855mL, 1.71 mmol) for 18 h. The reaction mixture was evaporated to removethe methanol. The residue was dissolved in water (20 mL) and acidifiedto pH4 with 2M HCl. The resulting white precipitate was recovered byfiltration, washed with water and dried under vacuum to give the titlecompound as a white solid (116 mg, 68%).

¹H NMR (300.073 MHz, DMSO-d₆) δ0.64 (3H, q), 1.14-1.26 (2H, m),1.67-1.76 (1H, m), 1.89-1.98 (2H, m), 2.42-2.59 (3H, m), 3.62-3.82 (1H,m), 3.93-4.01 (1H, m), 5.24-5.43 (1H, m), 7.43-7.48 (2H, m), 7.58-7.75(4H, m), 8.00-8.20 (3H, m), 13.18 (1H, s)

MS m/z 503 M+H

Example 74-[4-(Cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid

Methyl 4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate(363 mg, 0.94 mmol) (Intermediate #11) was dissolved in methanol (20 mL)and treated at ambient temperature with 2M aqueous sodium hydroxidesolution (2.35 mL). The mixture was stirred at ambient temperature for18 h and then volatiles were removed by evaporation under reducedpressure. The residue was dissolved in water (25 ml) and 2M HCl wasadded until the pH=4. The mixture was extracted with ethyl acetate (2×25mL) and the combined extracts were washed with water (2×10 mL) and brine(10 mL), dried (MgSO₄) and to evaporated to give the title product as awhite solid. (300 mg 85%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.68 (3H, t), 1.14-1.39 (7H, m),1.57-1.61 (1H, m), 1.72 (2H, d), 1.84 (2H, d), 2.70 (2H, t), 3.75-3.78(1H, m), 7.65-7.69 (2H, m), 7.90-7.93 (1H, m), 8.07-8.13 (2H, m), 8.14(1H, s), 13.20 (1H, s)

MS m/z 388 M+H

Example 83-[4-(Cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid

Methyl 3-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate(175 mg, 0.45), (Intermediate #12) was dissolved in methanol (10 mL),treated with 2M aqueous sodium hydroxide solution (1.125 mL) and stirredat ambient temperature for 18 h. Methanol was removed by evaporationunder reduced pressure and the clear solution diluted with water (25ml). 2M HCl was added to pH4 and the mixture extracted with ethylacetate (2×25 mL). The combined extracts were washed with water (2×10mL) and brine (10 mL), dried (MgSO₄) and evaporated to give the titleproduct as a white solid. (115 mg, 65%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.67 (3H, t), 1.14-1.39 (7H, m),1.57-1.61 (1H, m), 1.70 (2H, d), 1.82-1.85 (2H, m), 2.70 (2H, t),3.74-3.79 (1H, m), 7.66-7.71 (1H, m), 7.78-7.82 (1H, m), 7.91 (1H, d),8.03-8.06 (2H, m), 8.13 (1H, s), 13.29 (1H, s)

MS m/z 388 M+H

Example 9 4-[4-(Cyclohexylcarbamoyl)-5-propyl-pyrazol-1-yl]benzoic acid

Ethyl 4-[4-(cyclohexylcarbamoyl)-5-propyl-pyrazol-1-yl]benzoate (130 mg,0.34 mmol) (Intermediate #21) was dissolved in methanol (10 mL) andtreated at ambient temperature with 2M aqueous sodium hydroxide solution(2.5 mL). The mixture was stirred at ambient temperature for 18 h andthen methanol was removed by evaporation under reduced pressure. Theremaining aqueous solution was acidified with 2M aqueous hydrochloricacid to pH=2. A white solid precipitated out of solution, it wasfiltered, dried under vacuum and identified as the desired product (120mg, quantitative reaction).

¹H NMR (400.13 MHz, DMSO-d₆) δ0.73 (3H, t), 1.12 (1H, m), 1.23-1.31 (1H,m), 1.28 (3H, m), 1.36-1.43 (2H, m), 1.59-1.63 (1H, m), 1.73 (2H, d),1.80 (2H, s), 2.97 (2H, t), 3.73 (1H, m), 7.59-7.61 (2H, d), 7.95 (1H,d), 8.09-8.11 (2H, d), 8.21 (1H, s), 13.27 (1H, s)

MS m/z 356 M+H

Example 104-[4-(Cyclohexyl-methyl-carbamoyl)-5-propyl-pyrazol-1-yl]benzoic acid

Ethyl 4-[4-(cyclohexyl-methyl-carbamoyl)-5-propyl-pyrazol-1-yl]benzoate(Intermediate #23, 105 mg, 0.26 mmol) was dissolved in methanol (10 mL)and treated at ambient temperature with 2M aqueous sodium hydroxidesolution (2.5 mL). The mixture was stirred at ambient temperature for 18h and then methanol was removed by evaporation under reduced pressure.The remaining aqueous solution was acidified with 2M aqueoushydrochloric acid to pH=2. A white solid precipitated out of solution,it was filtered, dried under vacuum and identified as the desiredproduct (96 mg, quantitative reaction).

¹H NMR (400.13 MHz, DMSO-d₆) δ0.71 (3H, t), 1.12-1.50 (6H, m), 1.59-1.77(6H, m), 2.79 (2H, t), 2.89 (3H, s), 7.45-7.65 (1H, m), 7.67 (2H, d),7.84-7.86 (1H, m), 8.10 (2H, d), 13.24 (1H, s)

MS m/z 370 M+H

Example 11 4-[4-(cyclohexylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoicacid

1-(4-bromophenyl)-N-cyclohexyl-5-cyclopropyl-pyrazole-4-carboxamide(Intermediate #25) (111 mg, 0.29 mmol), molybdenum hexacarbonyl (38 mg,0.14 mmol), DMAP (70 mg, 0.57 mmol), DIPEA (74 mg, 0.57 mmol) andtrans-Di(-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) (14mg, 0.015 mmol) were added to a microwave vial and suspended in amixture of dioxan (2 mL) and ethanol (2 mL). The vial was capped andheated to 150° C. for 1 h. The reaction mixture was evaporated todryness and the residue dissolved in DCM (10 mL). 2 MHCl (10 ml) wasadded and the mixture shaken and passed through a phase separatingfilter. The DCM solution was dry loaded onto Ceelite and the productrecovered by flash chromatography on silica gel (elution gradient 0-50%EtOAc in Hexane). Pure fractions were combined and evaporated to givethe product as a white solid. The white solid was dissolved in methanol(5 mL), treated with 2M NaOH solution (1 mL) and stirred at ambienttemperature for 5 h. The reaction mixture was to concentrated underreduced pressure, diluted with water (20 mL), washed with ether (2×10mL), acidified to pH4 with 2M HCl and extracted with EtOAc (3×10 mL).The combined extracts were washed with water (10 mL), dried (MgSO4) andevaporated to afford4-[4-(cyclohexylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid aswhite solid. (40 mg, 40%)

The following Examples were prepared in a similar manner to Example #11,using an appropriate bromophenyl starting material:

MS m/e Structure Ex Name ¹H NMR δ MH⁺

12 4-[4-(2-adamantylcarbamoyl)- 5-cyclopropyl-pyrazol-1- yl]benzoic acid1H NMR (300.073 MHz, DMSO-d₆) δ 0.41-0.46 (2H, m), 0.85-0.91 (2H, m),1.56 (2H, d), 1.73 (2H, s), 1.85 (6H, d), 1.98 (2H, d), 2.08 (2H, d),2.21-2.30 (1H, m), 4.05 (1H, d), 7.58 (1H, d), 7.77 (2H, d), 7.94 (1H,s), 8.09 (2H, d) 406

13 4-[4-(1-adamantylcarbamoyl)- 5-cyclopropyl-pyrazol-1- yl]benzoic acid1H NMR (400.13 MHz, DMSO-d₆) δ 0.42-0.46 (2H, m), 0.87-0.92 (2H, m),1.67 (6H, s), 2.07 (9H, s), 2.14- 2.21 (1H, m), 7.17 (1H, s), 7.73-7.76(2H, m), 7.86 (1H, s), 8.07-8.10 (2H, m) 406

14 4-[4-(cyclohexyl-methyl- carbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid 1H NMR (300.073 MHz, DMSO-d₆) δ 0.45 (2H, s),0.83 (2H, d), 1.08-1.85 (10H, m), 2.06 (1H, s), 2.86 (3H, s), 3.57(0.4H, s), 4.15 (0.6H, s), 7.68 (1H, s), 7.82 (2H, d), 8.07 (2H, d),13.0 (1H, s) 368

15 4-[5-cyclopropyl-4-[(4- hydroxy-1- adamantyl)carbamoyl]pyrazol-1-yl]benzoic acid 1H NMR (400.13 MHz, DMSO-d₆) δ 0.42-0.46 (2H, m),0.85-0.90 (2H, m), 1.38 (2H, d), 1.65 (5H, d), 1.75 (2H, d), 1.96 (2H,d), 2.03 (1H, s), 2.08 (2H, s), 2.21- 2.28 (1H, m), 3.98 (1H, d), 4.40(1H, s), 7.53 (1H, d), 7.75-7.78 (2H, m), 7.94 (1H, s), 8.08-8.11 (2H,m), 13.1 (1H 422

Example 162-[4-[4-(Cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]aceticacid

Methyl2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetate(Intermediate #33) (210 mg, 0.51 mmol) was dissolved in methanol (10 mL)and treated at ambient temperature with a 2M solution of sodiumhydroxide (1.27 mL, 2.53 mmol). The mixture was stirred overnight andthen methanol was removed by evaporation under reduced pressure. Theclear aqueous solution was diluted with water (20 mL) and acidified topH3 with 2M HCl. The resulting white precipitate was extracted intoethyl acetate (2×20 mL). The combined extracts were washed with brine(10 mL), dried (MgSO4) and evaporated to give the crude product. Thecrude product was purified by to preparative HPLC using decreasinglypolar mixtures of water (containing 0.1% NH3) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]aceticacid. (84 mg, 41%).

1H NMR (400.13 MHz, DMSO-d₆) δ 0.72 (3H, t), 1.20-1.36 (7H, m), 1.60(1H, d), 1.73 (2H, d), 1.85 (2H, d), 2.69 (2H, t), 3.69 (2H, s), 3.77(1H, d), 7.42-7.47 (4H, m), 7.86 (1H, d), 8.10 (1H, s)

MS m/z (ESI+) (M+H)+ 402

Example 172-[4-[4-(2-Adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]aceticacid

Methyl2-[4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetate(Intermediate #34) (220 mg, 0.47 mmol) was dissolved in methanol (10 mL)and treated at ambient temperature with a 2M solution of sodiumhydroxide (1.17 mL, 2.35 mmol). The mixture was stirred overnight andthen methanol was removed by evaporation under reduced pressure. Theclear aqueous solution was diluted with water (20 mL) and acidified topH3 with 2M HCl. The resulting white precipitate was extracted intoethyl acetate (2×20 mL). The combined extracts were washed with brine(10 mL), dried (MgSO4) and evaporated to give the crude product. Thecrude product was purified by preparative HPLC using decreasingly polarmixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford2-[4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]aceticacid (66 mg, 31%).

1H NMR (400.13 MHz, DMSO-d₆) δ 0.70 (3H, t), 1.23-1.32 (2H, m), 1.62(2H, d), 1.74 (2H, s), 1.86 (6H, d), 1.99 (4H, d), 2.62 (2H, t), 3.70(2H, s), 4.11 (1H, d), 7.45 (2H, d), 7.50-7.52 (2H, m), 8.02 (1H, d),8.12 (1H, s)

MS m/z (ESI+) (M+H)+ 454

Example 184-(4-Cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoicacid

A solution of4-(4-Cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoicacid methyl ester (116 mg, 0.28 mmol) (Intermediate #40) and LiOH (47mg, 1.12 mmol) in MeOH (2 ml)/Water (1 ml) was stirred overnight atambient temperature. The bulk of the MeOH was removed in vacuo and theresulting solution was treated with citric acid (˜10 ml) then extractedwith EtOAc (2×˜15 ml). The organic layers were combined, washed withbrine (˜10 ml), dried (MgSO₄), filtered and evaporated to yield thetitle compound as a white solid (102 mg, 91%).

1H NMR (700.03 MHz, CDCl₃) δ 0.89 (3H, t), 1.22-1.30 (4H, m), 1.41-1.46(2H, m), 1.48-1.53 (2H, m), 1.62-1.64 (1H, m), 1.71-1.73 (1H, m),1.98-2.00 (2H, m), 2.56 (2H, t), 3.99-4.04 (1H, m), 5.59 (2H, s), 7.27(2H, d), 7.37 (1H, d), 8.05 (2H, d), 8.16 (1H, s)

MS m/e MH⁺ 402.

The following examples were made using the above procedure, replacing4-(4-Cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoicacid methyl ester with a corresponding starting material

Structure Example # Name NMR [M + H]+

19 3-(4- Cyclohexylcarbamoyl- 5-propylsulfanyl- pyrazol-1-ylmethyl)-benzoic acid 1H NMR (300.072 MHz, CDCl₃) δ 0.81-1.85 (3H, t), 1.11-1.31(3H, m), 1.35-1.52 (4H, m), 1.55-1.69 (3H, m), 1.87-1.98 (2H, m), 2.51(2H, t), 3.85-4.03 (1H, m), 5.51 (2H, s), 7.32-7.40 (3H, m), 7.94-7.99(2H, m), 8.09 (1H, s) 402

20 3-[4-(Adamantan-2- ylcarbamoyl)-5- propylsulfanyl-pyrazol-1-ylmethyl]- benzoic acid 1H NMR (300.072 MHz, CDCl₃) δ 0.82(3H, t), 1.39- 1.51 (2H, m), 1.57-1.73 (4H, m), 1.82 (8H, s), 1.96 (2H,s), 2.52 (2H, t), 4.20-4.28 (1H, m), 5.52 (2H, s), 7.34-7.41 (2H, m),7.90 (1H, d), 7.93- 7.99 (2H, m), 8.12 (1H, s) 454

21 4-[4-(Adamantan-2- ylcarbamoyl)-5- propylsulfanyl-pyrazol-1-ylmethyl]- benzoic acid 1H NMR (300.072 MHz, CDCl₃) δ 0.81(3H, t), 1.37- 1.49 (2H, m), 1.58-1.75 (4H, m), 1.82 (8H, s), 1.96 (2H,s), 2.50 (2H, t), 4.20-4.28 (1H, m), 5.53 (2H, s), 7.21 (2H, d), 7.89(1H, d), 7.99 (2H, d), 8.13 (1H, s) 454

Example 22 4-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoicacid

2M aqueous sodium hydroxide solution (51.7 mL, 103.32 mmol) was added tomethyl 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoate(Intermediate #56) (4.5 g, 10.33 mmol) in methanol (100 mL). The mixturewas stirred at 70° C. for 1 hour and then cooled to ambient temperature,concentrated under reduced pressure and diluted with water (100 mL). Thereaction mixture was adjusted to pH 3 with 2M HCl. The reaction mixturewas extracted with EtOAc (500 mL) and washed to sequentially with water(2×100 mL), and saturated brine (50 mL). The organic layer was driedover MgSO4, filtered and evaporated to give a pale yellow solid. Thesolid was washed with EtOAc (20 mL), collected by filtration and driedunder vacuum to give4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (3.89g, 89%) as a cream crystalline solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.19 (9H, s), 1.49 (2H, d), 1.70-1.96(10H, m), 2.09 (2H, d), 3.98-4.01 (1H, m), 7.49-7.53 (2H, m), 7.61 (1H,s), 8.06-8.09 (2H, m), 8.20 (1H, d), 13.30 (1H, s)

m/z (ESI+) (M+H)+=422

m.p. 308.8° C. (onset)

Example 22 may also be prepared as follows:

Aqueous sodium hydroxide (2M) (2.5 eq) was added portionwise over 5minutes to a stirred suspension of methyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoate(Intermediate #56) (1.0 eq) in methanol (10 vol) at 20° C. (exotherm20-27° C.). The resulting suspension was heated to 70° C. (jackettemperature), (batch refluxes approx 60-65° C.) for 1 hour (complete byLCMS). The orange reaction mixture was cooled to 20° C. (solutionremained slightly cloudy) and filtered through celite to remove a smallamount of solids. The filtrate was then poured into a flange flask andwater (25 vol) was added. The mixture was then adjusted to pH 3 with 2MHCl (approx 800-850 ml) (turns very thick). The aqueous was thenfiltered and the pale yellow solid washed with water, sucked dryovernight, and washed with acetonitrile and finally 1:1acetonotrile/diethyl ether and dried under vacuum at 50° C. for 72 hours(weekend) to give4-[4-(2-adamantylcarbamoyl)-5-tertbutyl-pyrazol-1-yl]benzoic acid (80%)as a solid.

Approximately 50 mg of4-[4-(2-adamantylcarbamoyl)-5-tertbutyl-pyrazol-1-yl]benzoic acid asprepared above (Form 1) was placed in a vial with a magnetic flea, andapproximately 2 ml of acetonitrile added. The vial was then sealedtightly with a cap. The slurry was then left to stir in a heated stirrerblock with magnetic stirring capabilities at 50° C. After 3 days, thesample was removed from the plate, the cap taken off and the slurry leftto dry under ambient conditions before it was analysed by XRPD and DSC.This form (Form 2) was determined to be crystalline by XRPD and seen tobe different to the previous form. This material had a melting point of310.3° C. (onset). It had 2 theta peaks measured using CuKa radiation at18.0 and 17.7.

Approximately 20 mg of4-[4-(2-adamantylcarbamoyl)-5-tertbutyl-pyrazol-1-yl]benzoic acid(form 1) was placed in a vial with a magnetic flea, and approximately 2ml of methanol added, the vial was then sealed tightly with a cap andleft to stir on a magnetic stirrer plate. After 3 days, the sample wasremoved from the plate, the cap taken off and the slurry left to dryunder ambient conditions before it was analysed by XRPD and DSC. Thisform (Form 3) was determined to be crystalline by XRPD and seen to bedifferent to previously seen forms. This material had a melting point of309.4° C. (onset). It had 2 theta peaks measured using CuKa radiation at18.7 and 11.7.

Approximately 20 mg of4-[4-(2-adamantylcarbamoyl)-5-tertbutyl-pyrazol-1-yl]benzoic acid asForm 1 and 20 mg of the Form 3 material was placed in a vial with amagnetic flea, and approximately 2 ml of ethyl acetate added, the vialwas then sealed tightly with a cap and left to stir on a magneticstirrer plate. After 3 days, the sample was removed from the plate, thecap taken off and the slurry left to dry under ambient conditions beforeit was analysed by XRPD and DSC. This form (Form 4) was determined to becrystalline by XRPD and seen to be different to previously seen forms.This material (Form 4) had a melting point of 309.1° C. (onset).). Ithad 2 theta peaks measured using CuKa radiation at 16.2 and 20.6

4-[4-(2-Adamantylcarbamoyl)-5-tertbutyl-pyrazol-1-yl]benzoic acid asprepared above (Form 1) was suspended in acetonitrile (7 vol), seededwith 5 g of (form 4) and slurried at reflux for 3 days (jackettemperature 85° C.). A sample was taken and checked by DSC (shows 2peaks). The sample was stirred at reflux for a further 3 days (weekend),cooled to 20° C., filtered, washed through with acetonitrile thendiethyl ether, sucked dry and dried under vacuum at 50° C. for 48 hoursto give a pale yellow solid (Form 4) (960 g, 90%).

Example 234-[4-(2-Adamantylcarbamoyl)-5-(1-methylcyclopropyl)pyrazol-1-yl]benzoicacid

A solution of aqueous 2N sodium hydroxide (8.45 mL, 16.90 mmol) wasadded to a stirred solution of methyl4-[4-(2-adamantylcarbamoyl)-5-(1-methylcyclopropyl)pyrazol-1-yl]benzoate(Intermediate #57), 1.221 g, 2.82 mmol) in methanol (25 mL) at roomtemperature. The resulting solution was stirred at 70° C. for 1 hour,and at room temperature overnight.

The reaction mixture was evaporated to dryness and re-dissolved in water(15 mL) and acidified with 2M HCl (10 mL). The reaction mixture was thenextracted into EtOAc (75 mL), and washed sequentially with water (10mL), and saturated brine (10 mL). The organic layer was dried overMgSO4, filtered and evaporated to afford4-[4-(2-adamantylcarbamoyl)-5-(1-methylcyclopropyl)pyrazol-1-yl]benzoicacid (1.055 g, 89%) as a white solid.

m/z (ESI+) (M+H)+=420; HPLC t_(R)=2.56 min.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.51-0.53 (2H, m), 0.68-0.69 (2H, m),1.54-1.58 (5H, m), 1.73 (2H, s), 1.84-1.87 (6H, m), 1.95-1.99 (2H, m),2.06 (2H, d), 4.03-4.09 (1H, m), 7.44 (1H, d), 7.67 (2H, d), 8.06 (1H,s), 8.11 (2H, d), 13.16 (1H, s)

Example 244-[4-(2-Adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoic acid

A solution of aqueous 2N sodium hydroxide (4.10 mL, 8.19 mmol) was addedto a stirred solution of methyl4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoate(Intermediate #62) 611 mg, 1.37 mmol) in methanol (15 mL) at room totemperature. The resulting solution was stirred at 70° C. for 1 hour.

The reaction mixture was evaporated to dryness and redissolved in water(15 mL) and acidified with 2M HCl (6 mL). The suspension obtained wasthen filtered. The product recovered was washed with water (10 mL) anddried under vacuum to give4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoic acid (576mg, 97%) as a white solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.43-1.55 (4H, m), 1.74-1.85 (12H, m),1.94 (2H, s), 2.03-2.12 (4H, m), 2.99-3.08 (1H, m), 3.98-4.03 (1H, m),7.53-7.55 (2H, m), 7.74 (1H, d), 8.09 (1H, s), 8.10-8.12 (2H, m), 13.30(1H, s)

m/z (ESI+) (M+H)+=434; HPLC t_(R)=2.80 min.

The same process as used for Example #24 prepared the following examplesfrom the appropriate intermediate.

MS m/e Structure Ex Name ¹H NMR δ MH⁺

25 4-[4-(2- adamantyl- carbamoyl)-5- ethylpyrazol- 1-yl]benzoic acid 1HNMR (400.13 MHz, DMSO-d₆) δ 1.03 (3H, t), 1.53 (2H, d), 1.72 (2H, s),1.78-1.85 (6H, m), 1.95 (2H, s), 2.11 (2H, d), 2.97 (2H, q), 4.04 (1H,t), 7.58-7.63 (3H, m), 8.09-8.13 (2H, m), 8.28 (1H, s) 394

26 4-[4-(2- adamantyl- carbamoyl)-5- propan-2- ylpyrazol-1- yl]benzoicacid 1H NMR (400.13 MHz, DMSO-d₆) δ 1.29 (6H, d), 1.52 (2H, d), 1.73(2H, s), 1.82 (5H, s), 1.86 (1H, s), 1.98 (2H, s), 2.11 (2H, d),3.10-3.17 (1H, m), 4.02-4.05 (1H, m), 7.54 (2H, d), 7.67 (1H, d), 8.07(1H, s), 8.11 (2H, d), 13.20 (1H, s) 408

27 4-[4-(2- adamantyl- carbamoyl)- 5-cyclobutyl- pyrazol-1- yl]benzoicacid 1H NMR (400.13 MHz, DMSO-d₆) δ 1.52 (2H, d), 1.65 (1H, q), 1.72(2H, s), 1.80-1.85 (7H, m), 1.96 (2H, s), 2.03-2.13 (4H, m), 2.20-2.28(2H, m), 3.76-3.85 (1H, m), 4.01-4.06 (1H, m), 7.52 (2H, d), 7.80 (1H,d), 7.93 (1H, s), 8.07 (2H, d), 13.40 (1H, s) 420

Example 28 4-[4-(2-Adamantylcarbamoyl)-5-methyl-pyrazol-1-yl]benzoicacid

A solution of 1M sodium hydroxide (24.28 mL, 24.28 mmol) was added to astirred suspension ofN-(2-adamantyl)-1-(4-cyanophenyl)-5-methyl-pyrazole-4-carboxamide(Intermediate #66) (1.25 g, 3.47 mmol) in dioxane (25 mL). The resultingsuspension was stirred at 100° C. for 7 hours. The reaction mixture wasconcentrated, diluted with water (40 mL) and filtered through Celite.The filtrates were acidified with 1M citric acid. The to precipitate wasrecovered by filtration, washed with water (3×20 mL) and dried undervacuum at 50° C. The crude product was purified by preparative HPLC(Phenomenex Gemini C18 110A (axia) column, 5 silica, 30 mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1%formic acid) and MeCN as eluents. Fractions containing the desiredcompound were evaporated to dryness to afford4-[4-(2-adamantylcarbamoyl)-5-methyl-pyrazol-1-yl]benzoic acid (550 mg,42%) as a pale yellow powder.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.45-1.54 (2H, m), 1.70-1.88 (8H, m),1.90-2.00 (2H, m), 2.05-2.18 (2H, m), 2.56 (3H, s), 4.00-4.10 (1H, m),7.57 (1H, d), 7.67 (2H, d), 8.11 (2H, d), 8.29 (1H, s), 13.25 (1H, s).

m/z (ESI+) (M+H)+=380;

Example 294-(5-tert-Butyl-4-(cyclohexylcarbamoyl)-1H-pyrazol-1-yl)benzoic acid

1-(4-bromophenyl)-5-tert-butyl-N-cyclohexyl-1H-pyrazole-4-carboxamide(Intermediate #82) (132 mg, 0.33 mmol), molybdenum hexacarbonyl (43.1mg, 0.16 mmol),trans-Di(-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II)(15.34 mg, 0.02 mmol), 4-Dimethylaminopyridine (80 mg, 0.65 mmol) andN-Ethyldiisopropylamine (0.113 mL, 0.65 mmol) were suspended in Dioxane(4 mL) and Water (1 mL) and sealed into a microwave tube. The reactionwas heated to 150° C. for 1 hour in the microwave to reactor and cooledto RT. The reaction mixture was diluted with DCM (20 mL) and water (10mL) and then adjusted to pH3 wih 2M HCl and filtered through celite. Theorganic layer was separated, dried over MgSO4, filtered and evaporatedto afford crude product.

The crude product was purified by preparative reverse phase HPLC usingdecreasingly polar mixtures of water (containing 0.1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford4-(5-tert-butyl-4-(cyclohexylcarbamoyl)-1H-pyrazol-1-yl)benzoic acid (18mg, 14.92%) as a white solid.

1H NMR (400.13 MHz, DMSO-d6) δ 1.15 (1H, s), 1.20 (9H, s), 1.25-1.4 (4H,m), 1.58 (1H, s), 1.71-1.74 (2H, m), 1.82 (2H, d), 3.18 (1H, s),7.48-7.50 (2H, m), 7.60 (1H, s), 8.05-8.10 (3H, m)

m/z (ESI+) (M+H)+=370

Example 304-[4-(2-Adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoicacid

2M aqueous sodium hydroxide (1.671 mL, 3.34 mmol) was added in oneportion to methyl4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoate(Intermediate #84) (330 mg, 0.67 mmol) in methanol (10 mL). Theresulting mixture was stirred at 20° C. for 18 hours. The reactionmixture was concentrated and diluted with water (50 mL), and washed withether (20 mL). The aqueous solution was adjusted to pH 3 with 2M HCl andextracted with EtOAc (2×25 mL), and the combined extracts washed tosequentially with water (2×20 mL) and saturated brine (20 mL). Theorganic layer was dried over MgSO4, filtered and evaporated to afford4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoicacid (321 mg, 100%).

1H NMR (400.13 MHz, DMSO-d6) δ 1.01-1.11 (5H, m), 1.41 (1H, s),1.50-1.57 (4H, m), 1.64 (2H, d), 1.75 (2H, s), 1.85 (6H, s), 1.93-2.05(4H, m), 2.94 (1H, s), 4.12 (1H, d), 7.72-7.76 (2H, m), 8.05 (1H, d),8.10-8.13 (2H, m), 8.18 (1H, s), 13.20 (1H, s)

m/z (ESI+) (M+H)+=480

The following Examples were prepared in a similar manner to Example #30,using an appropriate ester starting material

Structure Ex Name ¹H NMR δ MS m/e

31 4-[4-(1-adamantylcarbamoyl)- 5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic acid 1H NMR (400.13 MHz, DMSO-d6) δ 1.05-1.18 (5H, m), 1.42(1H, s), 1.56 (4H, d), 1.68 (6H, s), 2.07 (9H, s), 2.98 (1H, s), 7.53(1H, s), 7.68-7.71 (2H, m), 8.09-8.11 (3H, m), 13.19 (1H, s) (M − H)−478

32 4-[5-cyclohexylsulfanyl-4-[(5- hydroxy-2-adamantyl)carbamoyl]pyrazol- 1-yl]benzoic acid 1H NMR (400.13 MHz,DMSO-d6) δ 1.03-1.08 (5H, m), 1.41-1.56 (7H, m), 1.67 (4H, d), 1.76 (2H,d), 1.89 (2H, d), 2.08 (3H, s), 2.93 (1H, s), 4.03 (1H, d), 4.43 (1H,s), 7.73 (2H, d), 7.97 (1H, d), 8.10- 8.12 (2H, m), 8.18 (1H, s), 13.25(1H, s) (M + H)+ 496

33 4-[5-cyclohexylsulfanyl-4-[[5- (difluoromethoxy)-2-adamantyl]carbamoyl]pyrazol- 1-yl]benzoic acid 1H NMR (400.13 MHz,DMSO-d6) δ 1.03-1.08 (5H, m), 1.41-1.54 (7H, m), 1.93 (6H, d), 2.05 (2H,d), 2.18 (3H, d), 2.96 (1H, d), 4.10 (1H, t), 6.88 (1H, t), 7.73 (2H,d), 7.99 (1H, d), 8.12 (2H, d), 8.18 (1H, s), 13.20 (1H, s) (M + H)+ 546

Example 344-[4-(2-Adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoicacid

2M aqueous sodium hydroxide (1.694 mL, 3.39 mmol) was added in oneportion to methyl4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate(Intermediate #90) (325 mg, 0.68 mmol) in methanol (10 mL). Theresulting mixture was stirred at 20° C. for 18 hours. The reactionmixture was concentrated and diluted with water (50 mL), and washed withether (20 mL). The aqueous solution was adjusted to pH 3 with 2M HCl andextracted with EtOAc (2×25 mL), and the combined extracts washedsequentially with water (2×20 mL) and saturated brine (20 mL). Theorganic layer was dried over MgSO4, filtered and evaporated to afford4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoicacid (307 mg, 97%).

1H NMR (400.13 MHz, DMSO-d6) δ 1.17-1.25 (2H, m), 1.41 (4H, d), 1.65(4H, d), 1.74 (2H, s), 1.85 (6H, s), 1.96-2.02 (4H, m), 3.31-3.33 (1H,m), 4.12 (1H, d), 7.75-7.77 (2H, m), 8.08 (1H, d), 8.10-8.15 (2H, m),8.19 (1H, s), 13.20 (1H, s)

m/z (ESI+) (M+H)+=466

The following Examples were prepared in a similar manner to Example #34,using an appropriate ester starting material

MS m/e Structure Ex # Name ¹H NMR δ (M + H)+

35 methyl 4-[4-(1- adamantylcarbamoyl)- 5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate 1H NMR (400.13 MHz, DMSO-d6) δ 1.18-1.28 (2H, m),1.41-1.49 (4H, m), 1.64-1.71 (8H, m), 2.07 (9H, s), 3.32- 3.37 (1H, m),7.54 (1H, s), 7.70-7.73 (2H, m), 8.09-8.13 (3H, m), 13.20 (1H, s) 466

36 methyl 4-[5- cyclopentylsulfanyl-4- [[(1R,3S)-5-hydroxy-2-adamantyl]carbamoyl] pyrazol-1-yl]benzoate 1H NMR (400.13 MHz, DMSO-d6)δ 1.17-1.25 (2H, m), 1.36-1.47 (6H, m), 1.65 (6H, d), 1.76 (2H, d), 1.89(2H, d), 2.08 (3H, s), 3.35 (1H, d), 4.02- 4.05 (1H, m), 4.43 (1H, s),7.74-7.77 (2H, m), 7.99 (1H, d), 8.10-8.13 (2H, m), 8.18 (1H, s) 482

Example 374-[4-[[5-(Difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoicacid

2M aqueous sodium hydroxide (2.050 mL, 4.10 mmol) was added in oneportion to methyl4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoate(Intermediate #95) (459 mg, 0.82 mmol) in methanol (10 mL). Theresulting mixture was stirred at 20° C. for 18 hours and then a further4 hours at 55° C. The reaction mixture was concentrated and diluted withwater (50 mL), and washed with ether (20 mL). The aqueous solution wasadjusted to pH 3 with 2M HCl and extracted with EtOAc (2×25 mL), and thecombined extracts washed sequentially with water (2×20 mL) and saturatedbrine (20 mL). The organic layer was dried over MgSO4, filtered andevaporated to afford4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoicacid (284 mg, 63.5%).

1H NMR (400.13 MHz, DMSO-d6) δ 1.03-1.08 (5H, m), 1.41-1.54 (7H, m),1.93 (6H, d), 2.05 (2H, d), 2.18 (3H, d), 2.96 (1H, d), 4.10 (1H, t),6.88 (1H, t), 7.73 (2H, d), 7.99 (1H, d), 8.12 (2H, d), 8.18 (1H, s),13.20 (1H, s)

m/z (ESI+) (M+H)+=506

Example 384-[4-(Cyclohexylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoicacid

A solution of aqueous 2N sodium hydroxide (4 mL, 8 mmol) was added to astirred solution of methyl4-[4-(cyclohexylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate(Intermediate #96), 233 mg, 0.55 mmol) in methanol (7 mL) at roomtemperature. The resulting solution was stirred at room temperatureovernight.

The reaction mixture was evaporated to dryness and redissolved in water(15 mL) and acidified with 2M HCl (6 mL). The reaction mixture was thenextracted in EtOAc (30 mL), and washed sequentially with water (10 mL),and saturated brine (10 mL). The organic layer was dried over MgSO4,filtered and evaporated to afford4-[4-(cyclohexylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoicacid (217 mg, 96%) as a white solid.

m/z (ESI+) (M+H)+=414

1H NMR (400.13 MHz, DMSO-d₆) δ 1.21-1.45 (11H, m), 1.58-1.74 (5H, m),1.84-1.87 (2H, m), 3.42-3.48 (1H, m), 3.76-3.82 (1H, m), 7.70 (2H, d),7.90-7.92 (1H, d), 8.11 (2H, d), 8.16 (1H, s), 13.19 (1H, s)

Example 394-[4-(Cyclohexylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoicacid

4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoicacid was prepared from methyl4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanylpyrazol-1-yl]benzoate(Intermediate #97) by the same process used for Example #38

m/z (ESI+) (M+H)+=428; HPLC t_(R)=2.67 min.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.09 (4H, m), 1.19-1.30 (2H, m),1.33-1.41 (5H, m), 1.51-1.58 (5H, m), 1.71-1.75 (2H, m), 1.84-1.87 (2H,m), 3.03-3.12 (1H, m), 3.72-3.80 (1H, m), 7.71 (2H, d), 7.89-7.90 (1H,d), 8.09-8.11 (2H, m), 8.16 (1H, s), 13.20 (1H, s)

Example 404-[5-Cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoicacid

4-[5-cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoicacid was prepared from methyl4-[5-cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate(Intermediate #98) by the same process used for Example #38.

m/z (ESI+) (M+H)+=442

1H NMR (400.13 MHz, DMSO-d6) δ 1.16-1.52 (15H, m), 1.58-1.67 (3H, m),1.71-1.75 (2H, m), 1.84-1.87 (2H, m), 3.30 (1H, m), 3.78-3.81 (1H, m),7.67-7.70 (2H, d), 7.90 (1H, d), 8.09-8.12 (2H, d), 8.16 (1H, s), 13.18(1H, s)

Example 414-[4-(2-Adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoic acid

2M aqueous sodium hydroxide (2.446 mL, 4.89 mmol) was added in oneportion to methyl4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoate(Intermediate #99) (430 mg, 0.98 mmol) in methanol (20 mL). Theresulting mixture was stirred at 20° C. for 18 hours. The reactionmixture was concentrated, diluted with water (50 mL) and adjusted to pH3 with 2M HCl. The precipitate was collected by filtration, washed withwater (20 mL) and dried under vacuum to afford4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoic acid(383 mg, 92%) as a white solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.94 (3H, t), 1.63 (2H, d), 1.74 (2H, s),1.86 (6H, d), 1.99 (4H, d), 2.68 (2H, q), 4.11 (1H, t), 7.72-7.76 (2H,m), 8.04 (1H, d), 8.10-8.13 (2H, m), 8.19 (1H, s), 13.2 (1H, s)

m/z (ESI+) (M+H)+=426

Example 424-[4-(2-Adamantylcarbamoyl)-5-methylsulfanyl-pyrazol-1-yl]benzoic acid

Prepared from methyl4-[4-(2-adamantylcarbamoyl)-5-methylsulfanyl-pyrazol-1-yl]benzoate(Intermediate #100) by the same process as Example #41.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.61 (2H, d), 1.74 (2H, s), 1.86 (6H, d),2.00 (4H, d), 2.30 (3H, s), 4.11 (1H, t), 7.72-7.75 (2H, m), 8.01-8.04(1H, m), 8.10-8.14 (2H, m), 8.19 (1H, s), 13.2 (1H, s) m/z (ESI+)(M+H)+=412

Example 434-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoicacid

Lithium hydroxide monohydrate (27.5 mg, 0.65 mmol) was added to asuspension of4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoicacid methyl ester (Intermediate #105) (116 mg, 0.22 mmol) in methanol (4mL)/water (2 mL) at ambient temperature. The resulting suspension wasstirred at ambient temperature for 18 hours. The bulk of the organicsolvent was removed in vacuo and the resulting solution was diluted withwater (10 mL) and washed with ether (10 mL). The aqueous layer wasacidified to ˜pH4 with 2M HCl then extracted with EtOAc (3×25 ml). TheEtOAc layers were combined, washed sequentially with water (5 mL) andsaturated to brine (10 mL). The organic layer was dried over MgSO4,filtered and evaporated to afford4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoicacid (113 mg, 100%) as a white solid.

1H NMR (400.13 MHz, DMSO-d6) δ 0.68 (3H, t), 1.22-1.31 (2H, m), 1.57(2H, d), 1.96 (2H, s), 2.00-2.16 (7H, m), 2.20 (2H, s), 2.65 (2H, t),2.87 (3H, s), 4.09 (1H, m), 7.74 (2H, d), 8.05 (1H, d), 8.12 (2H, m),8.19 (1H, s), 13.20 (1H, s)

MS m/e MH⁺ 518.

Example 444-[4-(2-Adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-2-methoxy-benzoicacid

2M aqueous sodium hydroxide (1.256 mL, 2.51 mmol) was added in oneportion to methyl4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-2-methoxy-benzoate(Intermediate #106) (243 mg, 0.50 mmol) in methanol (10 mL). Theresulting mixture was stirred at 20° C. for 18 hours.

The reaction mixture was concentrated, diluted with water (50 mL) andadjusted to pH 3 with 2M HCl. The precipitate was collected byfiltration, washed with water (20 mL) and dried under vacuum to afford4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-2-methoxy-benzoicacid (202 mg, 86%) as a white solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.70 (3H, t), 1.23-1.32 (2H, m), 1.62(2H, d), 1.74 (2H, s), 1.86 (6H, d), 1.92-2.05 (4H, m), 2.65 (2H, t),3.87 (3H, s), 4.11 (1H, d), 7.23-7.25 (1H, m), 7.39 (1H, d), 7.81 (1H,d), 8.09 (1H, d), 8.17 (1H, s), 12.92 (1H, s)

m/z (ESI+) (M+H)+=470

Example 454-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoicacid

A solution of Sodium hydroxide (1.904 mL, 3.81 mmol) was added in oneportion to a stirred solution of ethyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoate(Intermediate #113) (353 mg, 0.76 mmol) in methanol (6 mL). Theresulting suspension was stirred at 20° C. for 16 hours. The resultingmixture was evaporated to remove the methanol and washed with ether (20mL). The reaction mixture was acidified with 2M HCl. The precipitate wascollected by filtration, washed with water (10 mL) and dried undervacuum to afford4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoicacid (266 mg, 80%) as a white solid.

¹H NMR (300.073 MHz, dmso) δ 1.16 (s, 9H), 1.50 (d, J=12.6 Hz, 2H), 1.70(s, 2H), 1.74-1.88 (m, 6H), 1.89-1.99 (m, 2H), 2.01-2.14 (m, 5H), 3.99(d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.86 (d, 1H), 7.94 (s, 1H), 8.05(d, 1H)

m/z (ESI+) (M+H)+=436

Example 464-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoicacid

4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoicacid was prepared from ethyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoate(Intermediate #117) by the same process used for Example #45.

1H NMR (400.13 MHz, CDCl₃) δ 1.29 (9H, s), 1.71-1.79 (6H, m), 1.91 (6H,s), 2.07 (2H, s), 4.24 (1H, d), 6.20 (1H, d), 7.63-7.66 (1H, m), 7.70(1H, s), 7.79-7.80 (1H, m), 8.00 (1H, d)

MS m/z (ESI+) (M+H)+=490.

Example 474-[4-(Adamantan-2-ylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzoicacid

A solution of Sodium hydroxide (1.056 mL, 2.11 mmol) was added in oneportion to a stirred solution ofN-adamantan-2-yl-1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide(Intermediate #124) (250 mg, 0.60 mmol), in methanol (10 mL) under air.The resulting solution was stirred at 65° C. for 45 hours. The resultingmixture was evaporated to dryness and the residue dissolved in ice/water(25 mL) and the mixture was acidified with 2M HCl. The precipitate wascollected by filtration, washed with water (25 mL) and dried undervacuum to afford4-[4-(adamantan-2-ylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzoicacid (243 mg, 93%) as a white solid, which was used without furtherpurification.

m/z (ESI+) (M+H)+=434; HPLC t_(R)=2.57 min.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.49-1.53 (2H, m), 1.71 (2H, s), 1.80(5H, s), 1.84 (1H, s), 1.93 (2H, s), 2.05 (2H, d), 3.98-4.05 (1H, m),7.63 (2H, d), 8.11-8.14 (3H, m), 8.34 (1H, d), 13.30 (1H, s)

Intermediate #14-[4-((1R,2S,3S,5S)-5-Hydroxy-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoicacid methyl ester

1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid(Intermediate #7) (160 mg, 0.5 mmol),(1S,3S,4S,5R)-4-Amino-adamantan-1-ol (84 mg, 0.5 mmol), HOBT (81 mg, 0.6mmol), and DIPEA (174 μL, 1 mmol) were dissolved in DMF (5 mL) andtreated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixturewas stirred at ambient for 18 h and then diluted with ethyl acetate (50mL), washed with water (3×20 mL) and brine, dried (MgSO₄) and evaporatedto leave a brown gum, which was purified by chromatography on silica gel(12 silica 0-100% EtOAc/isohexane) to give the title compound (159 mg,69%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.65 (3H, t), 1.17-1.29 (2H, m), 1.42(2H, d), 1.60-1.80 (6H, m), 1.89 (2H, d), 2.06 (3H, s), 2.62 (2H, t),3.90 (3H, s), 4.00 (1H, d), 4.43 (1H, s), 7.76 (2H, d), 7.95 (1H, d),8.13 (2H, d), 8.17 (1H, s)

MS m/z 470 M+H

Intermediate #2 Methyl4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate

1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid(Intermediate #7) (160 mg, 0.5 mmol), 2-adamantylamine hydrochloride (94mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (261 μL, 1.5 mmol) weredissolved in DMF (5 mL) and treated at ambient temperature with EDCI(115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and thendiluted with ethyl acetate (50 mL), washed with water (3×20 mL) andbrine, dried (MgSO₄) and evaporated to leave a white solid, which waspurified by chromatography on silica gel, (12 g silica 0-50%EtOAc/isohexane) to give the title compound as a white solid. (203 mg,92%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.65 (3H, t), 1.17-1.29 (2H, m), 1.60(2H, d), 1.73 (2H, s), 1.83 (6H, s), 1.91-2.05 (4H, m), 2.62 (2H, t),3.90 (3H, s), 4.09 (1H, d), 7.79 (2H, d), 8.03 (1H, d), 8.13 (2H, d),8.16 (1H, s)

MS m/z 454 M+H

Intermediate #3 Methyl4-[4-(1-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate

1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid(Intermediate #7) (160 mg, 0.5 mmol), 1-adamantylamine (76 mg, 0.5mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) weredissolved in DMF (5 mL) and treated at ambient temperature with EDCI(115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and thendiluted with ethyl acetate (50 mL), washed with water (3×20 mL) andbrine, dried (MgSO₄) and volatiles removed by evaporation. The residuewas purified by chromatography on silica gel (12 g silica 0-50%EtOAc/isohexane) to give the title compound as a colourless gum (143 mg,63%).

MS m/z 454 M+H

Intermediate #4 Methyl4-[4-(N-cyclohexyl-N-methyl-carbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate

1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid(Intermediate #7), (160 mg, 0.5 mmol), N-methylcyclohexylamine (57 mg,0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) weredissolved in DMF (5 mL) and treated at ambient temperature with EDCI(115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and thendiluted with ethyl acetate (50 mL), washed with water (3×20 mL) andbrine, dried (MgSO₄) and volatiles removed by evaporation. The residuewas purified by chromatography on silica gel (12 g silica 0-70%EtOAc/isohexane) to give the title compound as a colourless gum (162 mg,78%).

¹H NMR (300.073 MHz, DMSO-d₆) δ0.67 (3H, t), 1.01-1.41 (4H, m),1.42-1.85 (8H, m), 2.58 (2H, t), 2.86 (3H, s), 3.40-3.60 (0.5H, m), 3.89(3H, s), 4.20-4.40 (0.5H, m) 7.78 (2H, d), 7.91 (1H, s), 8.12 (2H, d)

MS m/z 416 M+H

Intermediate #5 Methyl4-[4-(oxan-4-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate

1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid(Intermediate #7), (160 mg, 0.5 mmol), 4-aminotetrahydropyran (61 mg,0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) weredissolved in DMF (5 mL) and treated at ambient temperature with EDCI(115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and thendiluted with ethyl acetate (50 mL), washed with water (3×20 mL) andbrine, dried (MgSO₄) and volatiles removed by evaporation. The residuewas purified by chromatography on silica gel (12 g silica, 0-100%EtOAc/isohexane) to give the title compound as a white solid (114 mg,56%).

¹H NMR (300.073 MHz, DMSO-d₆) δ0.68 (3H, t), 1.18-1.30 (2H, m),1.47-1.60 (2H, m), 1.77-1.81 (2H, m), 2.72 (2H, t), 3.36-3.43 (2H, m),3.81-3.89 (5H, m), 3.95-4.05 (1H, m), 7.71 (2H, d), 8.04 (1H, d), 8.12(2H, d), 8.17 (1H, s)

MS m/z 403 M+H

Intermediate #6 Methyl4-[5-propylsulfanyl-4-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl]pyrazol-1-yl]benzoate

1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid(Intermediate #7) was dissolved in DCM (3 mL). 1 drop of DMF and oxalylchloride to (71 μL, 0.83 mmol) was added. The mixture was stirred atambient temperature for 2 h and then volatiles were removed byevaporation under reduced pressure. The residue was dissolved in DCM (5mL) and added to a solution of 3-[2-(trifluoromethyl)phenyl]pyrrolidineHCl (105 mg, 0.42 mmol) and DIPEA (217 μL, 1.25 mmol) in DCM (5 mL).Water (10 mL) was added and the mixture stirred vigorously and passedthrough a phase separating column. The filtrate was purified bychromatography on silica gel, eluting with 0-20% EtOAc/DCM to give thetitle compound as a clear colourless oil (177 mg, 81%).

MS m/z 518 M+H

Intermediate #71-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid

tert-butyl1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylate(Intermediate #8) (2.86 g, 7.97 mmol) was dissolved in DCM (40 mL) andTFA (10 mL) added, the mixture was stirred at ambient temperature for 3h and then evaporated under reduced pressure to leave a light brown oil.Trituration of the oil with isohexane gave a light brown solid that wasrecovered by filtration and dried under vacuum to give the titlecompound. (2.23 g, 89%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.67 (3H, t), 1.20-1.32 (2H, m), 2.81(2H, t), 3.90 (3H, s), 7.71 (2H, d), 8.12 (2H, d), 8.17 (1H, s), 12.73(1H, s)

MS m/z 321 M+H

Intermediate #8 tert-butyl1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylate

tert-butyl 5-chloro-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate(Intermediate #9) (2.016 g, 6.0 mmol) was dissolved in butyronitrile (30mL), potassium carbonate (2.48 g, 18 mmol) and propanethiol (678 μL, 7.5mmol) were added and the mixture heated to reflux for 5 h. Ethyl acetate(150 mL) was added and the mixture washed with water (4×25 mL), dried(MgSO₄) and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel (120 g silica 0-25% EtOAc/isohexane) togive the title compound as a clear pale yellow oil that slowlycrystallised on standing to a white solid. (2.01 g, 89%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.67 (3H, t), 1.25 (2H, q), 1.54 (9H, s),2.76 (2H, t), 3.89 (3H, s), 7.70 (2H, d), 8.11 (3H, d)

MS m/z 321 M-tBut

Intermediate #9 tert-butyl5-chloro-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate

t-Butylnitrite (2.9 mL, 24.22 mmol) and cupric chloride (4.06 g, 30.27mmol) were added to acetonitrile (150 mL) and heated to 65° C.Tert-butyl 5-amino-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate(Intermediate #10) was added as a solid giving a vigorous gas evolution.After the addition was complete, heating was continued for a further 15min. The reaction mixture was cooled to ambient, diluted with water (500mL) and extracted with ethyl acetate (3×100 mL). The combined extractswere washed with water (2×100 mL) and brine (100 mL), dried (MgSO₄) andevaporated under reduced pressure. The residue was purified bychromatography on silica gel (120 g silica column, EtOAc/Hexane 0-50%)to give the title compound as an oil. (5.68 g, 83%)

¹H NMR (300.073 MHz, DMSO-d₆) δ1.53 (9H, s), 3.87-3.90 (3H, m), 7.78(2H, d), 8.15 (2H, d), 8.20 (1H, s)

MS m/z 281 M-tBut

Intermediate #10 Tert-butyl5-amino-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate

t-Butyl cyanoacetate (14.1 g, 100 mmol) was dissolved in triethylorthoformate (24.8 mL, 150 mmol). Acetic anhydride (9.625 mL, 100 mL)was added and the mixture heated to 125° C. for 3 h and then volatileswere removed by evaporation under reduced pressure. The residue wasdissolved in ethanol (100 mL) and methyl 4-hydrazinylbenzoatehydrochloride (Intermediate #123) (6.06 g, 30 mmol) and DIPEA (5.23 mL,30 mmol) was added. The mixture was heated to reflux for 5 h and thenevaporated under reduced pressure to leave a brown oil which wasdissolved in ethyl acetate (300 mL) and washed with water (2×100 mL) andbrine (100 mL), dried (MgSO₄) and evaporated. The residue was purifiedby chromatography on silica gel (120 g silica, EtOAc/Hexane 0-50%) togive the title compound as a yellow solid. (7.1 g)

¹H NMR (300.073 MHz, DMSO-d₆) δ1.51 (9H, s), 3.88 (3H, s), 6.43 (2H, s),7.67 (1H, s), 7.73 (2H, s), 8.08 (2H, d)

MS m/z 262 M-tBut

Intermediate #11 Methyl4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate

Propane thiol (88 mg, 1.16 mmol) was dissolved in DMF (5 mL) and treatedat ambient temperature with a 1M solution of NaHMDS in THF (1.16 mL).After stirring for 15 min the clear solution was added to a suspensionof methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate(Intermediate #15) (378 mg, 1.05 mmol) in DMF (10 mL). Stirring wascontinued at ambient temperature for 2 h and then the reaction mixturewas diluted with ethyl acetate (100 mL), washed with water (4×25 mL) anddried (MgSO₄). Volatiles were removed by evaporation under reducedpressure to give a clear oil which was purified by chromatography onsilica gel, eluting with an ethyl acetate/hexane gradient (0-50%) togive the title compound as a white solid. (363 mg, 86%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.67 (3H, t), 1.14-1.39 (7H, m), 1.59(1H, d), 1.71-1.74 (2H, m), 1.84 (2H, d), 2.70 (2H, t), 3.74-3.79 (1H,m), 3.89 (3H, s), 7.72 (2H, d), 7.92 (1H, d), 8.10-8.16 (3H, m)

MS m/z 402 M+H

Intermediate #12 Methyl3-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate

Propane thiol (48 mg, 0.57 mmol) was dissolved in DMF (3 mL) and treatedat ambient temperature with a 1M solution of NaHMDS in THF (0.63 mL,0.63 mmol). After stirring for 15 min a solution of methyl3-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#19) (205 mg, 0.57 mmol) in DMF (5 mL) was added and stirring continuedfor 2 h. Ethyl acetate (50 mL) was added and the mixture washed withwater (3×20 mL), dried (MgSO₄) and evaporated to give an oil which waspurified by chromatography on silica gel eluting with an EtOAc/DCMgradient (0-25%) to provide the title compound as a clear colourlessoil. (175 mg, 75%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.67 (3H, t), 1.14-1.39 (7H, m),1.57-1.61 (1H, m), 1.71-1.74 (2H, m), 1.84 (2H, d), 2.68-2.72 (2H, m),3.71-3.85 (1H, m), 3.89 (3H, s), 7.72 (1H, t), 7.83-7.94 (2H, m),8.05-8.08 (2H, m), 8.14 (1H, s)

MS m/z 402 M+H

Intermediate #15 methyl4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate

t-Butylnitrite (210 mg, 2.04 mmol) and cupric chloride (342 mg, 2.55mmol) were added to acetonitrile (15 mL) and heated to 65° C. Methyl4-[5-amino-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#16) (581 mg, 1.7 mmol) was added as a solid in portions giving avigorous gas evolution. After the addition was complete the reactionmixture was heated for a further 15 min. at 65° C., cooled to ambient,diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL).The combined extracts were washed with brine (2×20 mL), dried (MgSO₄)and evaporated to give a solid, which was purified by chromatography onsilica gel eluting with an EtOAc/Hexane to gradient (0-30%) to give thetitle compound as a white solid (385 mg, 65%)

¹H NMR (300.072 MHz, CDCl₃) δ1.21 (3H, d), 1.31-1.45 (2H, m), 1.57-1.71(3H, m), 1.93-1.98 (2H, m), 3.87-3.99 (4H, m), 6.02 (1H, d), 7.56-7.60(2H, m), 8.08-8.14 (3H, m)

MS m/z 362 M+H

Intermediate #16 Methyl4-[5-amino-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate

2-cyano-N-cyclohexyl-3-ethoxy-prop-2-enamide (Intermediate #17) (605 mg,2.73 mmol) and methyl 4-hydrazinylbenzoate hydrochloride (Intermediate#123) (552 mg, 2.73 mmol) were suspended in ethanol (20 mL). DIPEA (351mg, 2.73 mmol) was added and the mixture heated to 70° C. for 1 h. Thereaction mixture was cooled to ambient and the resulting precipitaterecovered by filtration, washed with ether and dried in vacuo to givethe title compound as a white solid. (618 mg 66%)

¹H NMR (300.073 MHz, DMSO-d₆) δ1.13 (1H, d), 1.22-1.35 (4H, m), 1.60(1H, d), 1.76 (4H, d), 3.69-3.74 (1H, m), 3.87 (3H, s), 6.56 (2H, s),7.62 (1H, d), 7.73-7.78 (2H, m), 8.04 (1H, s), 8.05-8.09 (2H, m)

MS m/z 343 M+H

Intermediate #17 2-cyano-N-cyclohexyl-3-ethoxy-prop-2-enamide

2-cyano-N-cyclohexyl-acetamide (Intermediate #18) (1.35 g, 8.09 mmol)was suspended in acetic anhydride (20 mL). Triethyl orthoformate (3.91g, 21 mmol) was added and the mixture heated to reflux for 5 h. Thereaction mixture was cooled to ambient and to volatiles removed byevaporation in vacuo to leave a brown oil which was which was purifiedby chromatography on silica gel eluting with an EtOAc/DCM gradient(0-10%) to give the title compound as a solid (637 mg, 35%)

¹H NMR (300.073 MHz, DMSO-d₆) δ1.01-1.35 (8H, m), 1.51-1.82 (5H, m),3.54-3.61 (1H, m), 4.32 (2H, q), 7.57 (1H, d), 8.11 (1H, t)

MS m/z 223 M+H

Intermediate #18 2-cyano-N-cyclohexyl-acetamide

Cyanoacetic acid (4.26 g, 50 mmol) and cyclohexylamine (4.96 g, 50 mmol)were dissolved in DCM (100 mL). EDCI (10.51 g, 55 mmol) was added andthe mixture stirred at ambient temperature for 24 h. The reactionmixture was washed with water (2×100 mL), dried (MgSO4) and evaporatedto leave a yellow solid residue which was purified by chromatography onsilica gel eluting with an EtOAc/DCM gradient (0-100%) to provide thetitle compound as a white solid (5.66 g, 68%).

¹H NMR (300.073 MHz, DMSO-d₆) δ1.06-1.32 (5H, m), 1.51-1.55 (1H, m),1.63-1.75 (4H, m), 3.46-3.57 (1H, m), 3.55 (2H, s), 8.06-8.09 (1H, m)

Intermediate #19 Methyl3-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate

t-Butylnitrite (145 mg, 1.38 mmol) and cupric chloride (236 mg, 1.76mmol) were added to acetonitrile (10 mL) and heated to 65° C. Methyl3-[5-amino-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#20) (400 mg, 1.38 mmol) was added as a solid in portions giving avigorous gas evolution. After the addition was complete heating wascontinued for a further 15 min. and then cooled to ambient, diluted withwater (50 mL) and extracted with ethyl acetate (3×25 mL). The combinedextracts were washed with water (2×20 mL), dried (MgSO₄) and evaporatedto give a brown oil which was purified by chromatography on silica geleluting with an EtOAc/Hexane gradient (0-50%) to provide the titlecompound as a clear colourless oil. (256 mg, 51%)

¹H NMR (400.13 MHz, CDCl₃) δ1.15-1.25 (3H, m), 1.32-1.43 (2H, m), 1.58(1H, d), 1.65-1.71 (2H, m), 1.94-1.98 (2H, m), 3.89 (3H, s), 3.91-3.98(1H, m), 6.04 (1H, d), 7.55 (1H, t), 7.66-7.68 (1H, m), 8.08-8.10 (2H,m), 8.15 (1H, t)

MS m/z 360 M−H

Intermediate #20 Methyl3-[5-amino-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate

2-cyano-N-cyclohexyl-3-ethoxy-prop-2-enamide (Intermediate #17) (605 mg,2.73 mmol) and methyl 3-hydrazinylbenzoate hydrochloride (552 mg, 2.73mmol) were suspended in ethanol (20 mL). DIPEA (352 mg, 2.73 mmol) wasadded and the mixture heated to 70° C. for 1 h. The reaction mixture wascooled to ambient and concentrated to a small volume. Water (50 mL) wasadded and the resulting solid recovered by filtration, redissolved inethyl acetate (50 mL), dried (MgSO₄) and evaporated to give a brownsolid which was slurried with ether and recovered by filtration to givethe title compound as light brown solid (443 mg, 47%).

¹H NMR (300.073 MHz, DMSO-d₆) δ1.20 (5H, d), 1.61 (1H, d), 1.72-1.75(2H, m), 1.80 (2H, d), 3.70-3.74 (1H, m), 3.88 (3H, s), 6.47 (2H, s),7.59-7.69 (2H, m), 7.84-7.88 (1H, m), 7.91-7.94 (1H, m), 8.01 (1H, s),8.12 (1H, t)

MS m/z 343 M+H

Intermediate #21 Ethyl4-[4-(cyclohexylcarbamoyl)-5-propyl-pyrazol-1-yl]benzoate

1-(4-chlorophenyl)-N-cyclohexyl-5-propyl-pyrazole-4-carboxamide(Intermediate #22) (159 mg, 0.46 mmol), Molybdenum hexacarbonyl (61 mg,0.23 mmol), Herrmann's catalyst(Trans-Di-Mu-Acetatobis[2-(Di-O-Tolylphosphino)Benzyl]dipalladium(II),22 mg, 0.02 mmol), DMAP (113 mg, 0.92 mmol), DIPEA (161 μL, 0.92 mmol),Fu's salt (Tri-(T-Butyl)Phosphonium Hydrogen tetrafluoroborate Salt, 27mg, 0.09 mmol), Dioxane (2 mL), Ethanol (2 L) were mixed into amicrowave tube. The reaction mixture was then heated at 150° C. for 1hour by microwave. LC-MS showed complete conversion to the product. Thesolvent was evaporated under reduced pressure and the reaction mixtureextracted with EtOAc (2×25 mL), washed with water (10 mL), 2N HCl (10mL) and brine (10 mL). The organic phase was dried over MgSO₄ andevaporated under reduced pressure to give a black gum. The residue waspurified by column chromatography (12 g silicycle column, gradient: 1:0to 1:1 hexane/EtOAc) and appropriate fractions combined and concentratedin vacuo to yield the desired compound as a white solid (130 mg, 74%).

¹H NMR (400.13 MHz, CDCl₃) δ0.76-0.81 (3H, t), 1.09-1.21 (3H, m), 1.36(5H, m), 1.45-1.55 (2H, m), 1.61 (1H, m), 1.67-1.72 (2H, m), 1.96-1.98(2H, m), 2.89-2.93 (2H, m), 3.85-3.92 (1H, m), 4.35 (2H, q), 5.62 (1H,d), 7.41-7.44 (2H, m), 7.71 (1H, s), 8.10-8.13 (2H, m)

MS m/z 384 M+H

Intermediate #221-(4-chlorophenyl)-N-cyclohexyl-5-propyl-pyrazole-4-carboxamide

To a suspension of 1-(4-chlorophenyl)-5-propyl-pyrazole-4-carbonylchloride (commercially available, 302 mg, 1.07 mmol) in DCM (5 ml) wasadded 1 drop of DMF followed by cyclohexylamine (306 μL, 2.68 mmol). Thereaction mixture was stirred at room temperature for two hours thenstopped.

It was extracted in DCM (10 mL), washed with 2N NaOH (5 mL), 2N HCl (5mL), water (mL) and brine (5 mL). The organic phase was dried over MgSO₄and evaporated under reduced pressure to give a white solid (200 mg,54%), which was used without to further purification.

¹H NMR (400.13 MHz, DMSO-d₆) δ0.73 (3H, t), 1.13 (1H, d), 1.22-1.31 (4H,m), 1.35-1.44 (2H, m), 1.60-1.63 (1H, m), 1.69-1.75 (2H, m), 1.80-1.82(2H, m), 2.91 (2H, t), 3.72-3.75 (1H, m), 7.48-7.52 (2H, m), 7.61-7.64(2H, m), 7.84 (1H, d), 8.13 (1H, s)

MS m/z 346 M+H

Intermediate #23 Ethyl4-[4-(cyclohexyl-methyl-carbamoyl)-5-propyl-pyrazol-1-yl]benzoate

1-(4-chlorophenyl)-N-cyclohexyl-N-methyl-5-propyl-pyrazole-4-carboxamide(Intermediate #24), 101 mg, 0.28 mmol), Molybdenum hexacarbonyl (37 mg,0.14 mmol), Herrmann's catalyst(Trans-Di-Mu-Acetatobis[2-(Di-O-Tolylphosphino)Benzyl]dipalladium(II),14 mg, 0.01 mmol), DMAP (69 mg, 0.56 mmol), DIPEA (98 μL, 0.56 mmol),Fu's salt (Tri-(T-Butyl)Phosphonium Hydrogen tetrafluoroborate Salt, 17mg, 0.06 mmol), Dioxane (2 mL), Ethanol (2 mL) were mixed into to amicrowave tube. The reaction mixture was then heated at 150° C. for 1hour by microwave.

LC-MS showed complete conversion to the product. The same reaction wasrepeated in another microwave tube and the two reaction mixtures werecombined for work up and purification. The solvent was evaporated underreduced pressure and the reaction mixture extracted with EtOAc (2×25mL), washed with water (10 mL), 2N HCl (10 mL) and brine (10 mL). Theorganic phase was dried over MgSO₄ and evaporated under reduced pressureto give a black gum. The residue was purified by column chromatography(12 g silicycle column, gradient: 1:0 to 1:1 hexane/EtOAc) andappropriate fractions combined and concentrated in vacuo to yield thedesired compound as a white solid (105 mg, 61%).

¹H NMR (400.13 MHz, CDCl₃) δ0.71-0.79 (3H, t), 1.02-1.10 (1H, m), 1.19(2H, t), 1.31-1.40 (5H, m), 1.55-1.72 (4H, m), 1.75-1.78 (2H, m),2.73-2.79 (2H, m), 2.89 (3H, m), 4.05 (1H, q), 4.35 (2H, q), 6.99-7.11(1H, m), 7.46 (2H, d), 7.55 (1H, s), 8.10-8.13 (2H, d)

MS m/z 398 M+H

Intermediate #241-(4-chlorophenyl)-N-cyclohexyl-N-methyl-5-propyl-pyrazole-4-carboxamide

To a suspension of 1-(4-chlorophenyl)-5-propyl-pyrazole-4-carbonylchloride (commercially available, 302 mg, 1.07 mmol) in DCM (5 ml) wasadded 1 drop of DMF followed by N-methylcyclohexylamine (349 μL, 2.68mmol). The reaction mixture was to stirred at room temperature for twohours then stopped.

It was extracted in DCM (10 mL), washed with 2N NaOH (5 mL), 2N HCl (5mL), water (5 mL) and brine (5 mL). The organic phase was dried overMgSO₄ and evaporated under reduced pressure to give a colourless gum(263 mg, 73%), which was used without further purification.

¹H NMR (400.13 MHz, DMSO-d₆) δ0.70 (3H, t), 1.20-1.46 (5H, m), 1.58-1.63(5H, m), 1.76-1.79 (2H, m), 2.73-2.74 (3H, m), 2.89 (4H, m), 7.54-7.57(2H, m), 7.61-7.64 (2H, m)

MS m/z 360 M+H

Intermediate #251-(4-bromophenyl)-N-cyclohexyl-5-cyclopropyl-pyrazole-4-carboxamide

1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylic acid (Intermediate#30) (237 mg, 0.77 mmol) was suspended in DCM (5 mL). One drop of DMFwas added and then oxalyl chloride (200 μL, 2.32 mmol) was added slowly.The reaction mixture was stirred at ambient temperature for 4 h and thenevaporated under reduced pressure. The residue was to dissolved in DCM(5 mL) and added to a solution of cyclohexylamine (97 μL, 0.85 mmol) andDIPEA (403 μL, 2.32 mmol) in DCM (5 mL). The mixture was stirred atambient for 24 h and then water, (10 mL) was added and the mixturepassed through a phase separating filter. The product was recovered fromthe filtrate by flash column chromatography (SiO2, elution gradient0-100% EtOAc in isohexane). Pure fractions were combined and evaporatedto give1-(4-bromophenyl)-N-cyclohexyl-5-cyclopropyl-pyrazole-4-carboxamide aswhite solid. (277 mg, 92%)

¹H NMR (400.13 MHz, DMSO-d₆) δ0.39-0.43 (2H, m), 0.84-0.89 (2H, m),1.12-1.20 (1H, m), 1.24-1.36 (4H, m), 1.61 (1H, d), 1.69-1.75 (2H, m),1.87 (2H, d), 2.14-2.21 (1H, m), 3.72-3.77 (1H, m), 7.73-7.79 (3H, m),7.92-7.98 (1H, m), 8.07-8.10 (2H, m), 13.17 (1H, s)

MS m/z (ESI+) (M+H)+ 390

The following intermediates were prepared from1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylic acid (Intermediate#30) in a similar manner to Intermediate #25, using the appropriateamine starting material:

MS m/e Structure Int. # Name ¹H NMR δ MH⁺

26 N-(2-adamantyl)-1- (4-bromophenyl)-5- cyclopropyl- pyrazole-4-carboxamide ¹H NMR (300.073 MHz, DMSO-d₆) δ 0.41-0.46 (2H, m), 0.79-0.88(2H, m), 1.54 (2H, d), 1.72 (2H, s), 1.83 (6H, d), 1.94 (2H, s), 2.05(2H, d), 2.13-2.22 (1H, m), 4.04 (1H, d), 7.52 (1H, d), 7.56 (2H, d),7.73 (2H, d), 7.89 (1H, s) 440

27 N-(1-adamantyl)-1- (4-bromophenyl)-5- cyclopropyl- pyrazole-4-carboxamide ¹H NMR (300.073 MHz, DMSO-d₆) δ 0.41-0.46 (2H, m), 0.83-0.89(2H, m), 1.65 (6H, s), 2.05 (9H, s), 2.08-2.14 (1H, m), 7.13 (1H, s),7.51- 7.56 (2H, m), 7.69-7.74 (2H, m), 7.81 (1H, s) 440

28 1-(4-bromophenyl)- N-cyclohexyl-5- cyclopropyl-N- methyl-pyrazole-4-carboxamide ¹H NMR (300.073 MHz, DMSO-d₆) δ 0.35-0.55 (2H, m) 0.79-0.81(2H, m), 1.11-1.23 (2H, m), 1.33 (1H, s), 1.55 (2H, s), 1.61-1.65 (3H,m), 1.76 (2H, s), 1.98 (1H, s), 2.85 (3H, s), 3.43- 3.70 (0.4H, s), 4.31(0.6H, s), 7.63 (3H, d), 7.72 (2H, d) 402

29 1-(4-bromophenyl)- 5-cyclohexyl-N-(4- hydroxy-1- adamantyl)pyrazole-4-carboxamide 1H NMR (400.13 MHz, DMSO-d₆) δ 0.43-0.47 (2H, m),0.83-0.88 (2H, m), 1.38 (2H, d), 1.65 (4H, d), 1.75 (2H, d), 1.95 (2H,d), 2.03-2.08 (3H, m), 3.97 (1H, t), 4.39 (1H, s), 7.47-7.49 (1H, m),7.56-7.59 (2H, m), 7.72-7.76 (2H, m), 7.91 (1H, s) 458

Intermediate #30 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylicacid

Ethyl 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylate(Intermediate #31) (423 mg, 1.29 mmol) was dissolved in methanol (20 mL)and treated with 2M aqueous sodium hydroxide solution (3.23 mL, 6.46mmol). The mixture was stirred at ambient temperature for 24 h and thenthe methanol was removed by evaporation under reduced pressure. Theresidue was dissolved in water (50 mL), acidified to pH4 with 2M HCl andextracted with EtOAc (3×25 mL). The combined extracts were washed withwater and brine, dried (MgSO4) and evaporated to leave1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylic acid a whitesolid. (343 mg, 87%).

¹H NMR (300.073 MHz, DMSO-d₆) δ0.46-0.57 (2H, m), 0.82-0.87 (2H, m),1.98-2.11 (1H, m), 7.55-7.62 (2H, m), 7.71-7.75 (2H, m), 7.94 (1H, s),12.32 (1H, s)

MS m/z (ESI+) (M+H)+ 309

Intermediate #31 Ethyl1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylate

Ethyl-2-(cyclopropanecarbonyl)-3-dimethylamino-prop-2-enoate(Intermediate #32) (316 mg, 1.5 mmol) was dissolved in ethanol (5 mL).4-bromophenylhydrazine hydrochloride (335 mg, 1.5 mmol) and DIPEA (264μL, 1.5 mmol) were added and the mixture was heated to reflux for 2 h.The reaction mixture was cooled to ambient and evaporated under reducedpressure. The residue was dissolved in DCM (10 mL) washed with water andpoured through a phase separating tube. The product was recovered fromthe filtrate by flash column chromatography (SiO2, elution gradient0-25% EtOAc in isohexane). Pure fractions were combined and evaporatedto give ethyl 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylate asan oil that crystallised on standing. (343 mg, 87%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.43-0.49 (2H, m), 0.84-0.90 (2H, m),1.29 (3H, t), 2.05-2.14 (1H, m), 4.24 (2H, q), 7.55-7.60 (2H, m),7.71-7.76 (2H, m), 7.98 (1H, d)

MS m/z (ESI+) (M+) 335

Intermediate #32Ethyl-2-(cyclopropanecarbonyl)-3-dimethylamino-prop-2-enoate

Ethyl 3-cyclopropane-3-oxopropionionate (312 mg, 2 mmol) andN,N-dimethylformamide dimethylacetal (402 μL, 3 mmol) were dissolved indioxan (5 mL) and heated to reflux for 2 h. The reaction mixture wascooled to ambient and evaporated under to reduced pressure to leave ayellow oil, which was purified by flash column chromatography (SiO2,elution gradient 0-100% EtOAc in isohexane). Pure fractions werecombined and evaporated to giveethyl-2-(cyclopropanecarbonyl)-3-dimethylamino-prop-2-enoate as an oil.(316 mg, 74%)

¹H NMR (300.073 MHz, DMSO-d₆) δ0.69-0.80 (4H, m), 1.15-1.24 (3H, m),2.26-2.34 (1H, m), 2.94 (6H, s), 4.11 (2H, q), 7.57 (1H, s)

MS m/z (ESI+) (M+H)+ 212

Intermediate #33 Methyl2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetate

1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylicacid (Intermediate #35) (220 mg, 0.66 mmol) was dissolved in DCM (5 mL)and 1 drop of DMF added. Oxalyl chloride (176 μL, 1.96 mmol) was addedand the mixture stirred at ambient temperature for 3 h. Volatiles wereremoved by evaporation under reduced pressure and the resulting gumre-dissolved in DCM (2 mL) and added at ambient temperature to asolution of cyclohexylamine (66 mg, 0.66 mmol) and DIPEA (230 μL, 1.32mmol) in DCM (5 mL). The reaction mixture was stirred at ambienttemperature for 2 h, diluted with EtOAc (50 mL) and washed with water(2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated under reducedpressure. The residue was purified by flash chromatography on to silicagel (elution gradient 0-100% EtOAc in isohexane) to afford methyl2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetateas a white solid. (220 mg, 88%)

1H NMR (300.073 MHz, DMSO-d₆) δ 0.69 (3H, t), 1.20-1.32 (7H, m), 1.58(1H, d), 1.69-1.74 (2H, m), 1.83 (2H, d), 2.68 (2H, t), 3.64 (3H, s),3.74-3.82 (1H, m), 3.80 (2H, s), 7.44 (4H, s), 7.84-7.89 (1H, m), 8.08(1H, s)

MS m/z (ESI+) (M+H)+ 416

Intermediate #34 Methyl2-[4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetate

Prepared from1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylicacid (Intermediate #35) and 2-adamantylamine hydrochloride by the sameprocedure as used for Intermediate #6.

1H NMR (300.073 MHz, DMSO-d₆) δ 0.67 (3H, t), 1.15-1.31 (2H, m), 1.61(2H, d), 1.73 (2H, s), 1.83 (6H, s), 1.96 (4H, d), 2.61 (2H, t), 3.64(3H, s), 3.80 (2H, s), 4.09 (1H, d), 7.40-7.52 (4H, m), 8.02 (1H, d),8.11 (1H, s)

MS m/z (ESI+) (M+H)+ 468

Intermediate #351-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylicacid

tert-butyl1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylate(Intermediate #36) was dissolved in DCM (10 mL). TFA (2 mL) was addedand the mixture was stirred at ambient temperature for 5 h. Volatileswere then evaporated under reduced pressure and the residue dried undervacuum to afford1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylicacid as a light brown oil. (440 mg, 98%)

1H NMR (300.073 MHz, DMSO-d₆) δ 0.70 (3H, t), 1.21-1.33 (2H, m), 2.79(2H, t), 3.64 (3H, s), 3.80 (2H, s), 7.44 (4H, s), 8.10 (1H, s)

Intermediate #36 tert-butyl1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylate

tert-butyl5-chloro-1-[4-(methoxycarbonylmethyl)phenyl]pyrazole-4-carboxylate(Intermediate #37) (767 mg, 2.19 mmol) was dissolved in butyronitrile(10 mL). Potassium carbonate (906 mg, 6.57 mmol) and propanethiol (284μL, 2.74 mmol) were added and the mixture heated at 90° C. for 18 h. Thereaction mixture was cooled to ambient and ethyl acetate (50 mL) wasadded. The mixture was washed with water (4×25 mL), dried (MgSO4) andevaporated under reduced pressure. The residue was purified by flashchromatography on silica gel (elution gradient 0-25% EtOAc in isohexane)to afford tert-butyl1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylateas a yellow oil. (527 mg, 62%).

1H NMR (300.073 MHz, DMSO-d₆) δ 0.70 (3H, t), 1.27 (2H, q), 1.53-1.54 (9s, 2.75 (2H, t), 3.64 (3H, s), 3.80 (2H, s), 7.44 (4H, s), 8.07-8.12(1H, m)

MS m/z (ESI+) (M+H)+ 391

Intermediate #37 tert-butyl5-chloro-1-[4-(methoxycarbonylmethyl)phenyl]pyrazole-4-carboxylate

t-Butylnitrite (419 μL, 3.49 mmol) and copper (2) chloride (585 mg, 4.37mmol) were added to acetonitrile (10 mL) and heated to 65° C. Tert-butyl5-amino-1-[4-(methoxycarbonylmethyl)phenyl]pyrazole-4-carboxylate(Intermediate #38) (965 mg, 2.91 mmol) was added as a solution inacetonitrile (5 mL) giving a vigorous gas evolution. After the additionwas complete heating was continued for a further 15 min. The reactionmixture was cooled to ambient, diluted with water (50 mL) and extractedwith ethyl acetate (3×50 mL). The combined extracts were washed withwater (2×50 mL) and brine (10 mL), dried (MgSO4) and evaporated to givea brown oil which was purified by to flash chromatography on silica gel(elution gradient 0-50% EtOAc in isohexane) to give the title compoundas a yellow oil. (785 mg, 77%)

1H NMR (300.073 MHz, DMSO-d₆) δ 1.52 (9H, s), 3.62-3.64 (3H, m), 3.81(2H, s), 7.48-7.54 (4H, m), 8.12 (1H, s)

MS m/z (ESI+) (M+H)+ 351

Intermediate #38 tert-butyl5-amino-1-[4-(methoxycarbonylmethyl)phenyl]pyrazole-4-carboxylate

t-Butyl cyanoacetate (3.525 g, 25 mmol) was dissolved in triethylorthoformate (6.2 mL, 37.5 mmol). Acetic anhydride (2.41 mL, 25 mmol)was added and the mixture heated to 125° C. for 3 h. Volatiles were thenremoved by evaporation under reduced pressure to leave an orange oil.The crude oil was dissolved in methanol and methyl2-(4-hydrazinylphenyl)acetate hydrochloride (Intermediate #39) (1.62 g,7.5 mmol) and DIPEA (1.3 mL, 7.5 mmol) were added. The mixture washeated to reflux for 2 h and then evaporated to dryness. The residue wasdissolved in ethyl acetate (100 mL), washed with water (2×50 mL) andbrine (50 mL), dried (MgSO4) and evaporated to leave a crude to productwhich was purified by flash chromatography on silica gel (elutiongradient 0-50% EtOAc in isohexane) to give the title compound as ayellow solid. (974 mg, 39%)

1H NMR (300.073 MHz, DMSO-d₆) δ 1.51 (9H, d), 3.63 (3H, s), 3.76 (2H,s), 6.20 (2H, s), 7.41 (2H, d), 7.48 (2H, d), 7.60 (1H, s)

MS m/z (ESI+) (M+H)+ 331

Intermediate #39 methyl 2-(4-hydrazinylphenyl)acetate hydrochloride

A solution of methyl 4-iodophenylacetate (4.25 g, 15.39 mmol) wasdissolved in DMF (25 mL). BOC-carbazate (2.44 g, 18.47 mmol),1,10-phenanthroline (278 mg, 1.54 mmol), copper iodide (147 mg, 0.77mmol) and cesium carbonate (7.0 g, 21.55 mmol) were added and themixture heated at 120° C. for 60 min. The reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water (3×10 mL) and brine (10mL), dried (MgSO4) and evaporated to leave a brown oil which waspurified by flash chromatography on silica gel (elution gradient 0-50%EtOAc in isohexane) to give a colourless oil. The oil was dissolved in4M HCl Dioxan (20 mL) and stirred at ambient temperature for 3 h givinga thick precipitate. Diethyl ether (100 mL) was added and theprecipitate recovered by filtration, washed with ether (2×20 mL) anddried under vacuum to leave methyl2-(4-hydrazinylphenyl)acetate_hydrochloride as a light brown solid.(1.63 g, 49%)

1H NMR (300.073 MHz, DMSO-d₆) δ 3.59 (5H, s), 6.93 (2H, d), 7.16 (2H,d), 8.21 (1H, s), 10.20 (3H, s)

Intermediate #403-(4-Cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoicacid methyl ester

A solution of1-(4-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylicacid (Intermediate #44) (118 mg, 0.35 mmol), cyclohexylamine (49 μl,0.42 mmol), EDAC (75 mg, 0.39 mmol) and DMAP (9 mg, 0.07 mmol) in DCM (5ml) was stirred overnight at ambient temperature. The solvent wasevaporated in vacuo and the resulting residue was partitioned betweenEtOAc (˜30 ml) and citric acid (˜20 ml). The layers were separated andthe aqueous layer was re-extracted with EtOAc (˜10 ml). The combinedorganic layers were washed with brine (˜10 ml) then dried (MgSO₄),filtered and evaporated to yield an oil. The oil was purified by columnchromatography (4 g Si, eluting with 20 to 60% EtOAc in 1H) to yield thetitle compound as a pale yellow oil (116 mg, 79%).

¹H NMR (300.072 MHz, CDCl₃) δ0.81 (3H, t), 1.13-1.25 (3H, m), 1.30-1.48(4H, m), 1.52-1.69 (3H, m), 1.89-1.94 (2H, m), 2.47 (2H, t), 3.83 (3H,s), 3.88-3.98 (1H, m), 5.49 (2H, s), 7.18 (2H, d), 7.24 (1H, d), 7.92(2H, d), 8.07 (1H, s)

MS m/e MH⁺ 416.

The following intermediates were made by the above procedure using thecorresponding starting materials

Structure Intermediate # Name NMR [M + H]+

41 3-(4- Cyclohexylcarbamoyl- 5-propylsulfanyl- pyrazol-1-ylmethyl)-benzoic acid methyl ester ¹H NMR (300.072 MHz, CDCl₃) δ 0.82 (3H, t),1.13- 1.26 (3H, m), 1.30-1.50 (4H, m), 1.50-1.70 (3H, m), 1.85- 1.95(2H, m), 2.48 (2H, t), 3.84 (3H, s), 3.88-3.96 (1H, m), 5.48 (2H, s),7.31-7.34 (3H, m), 7.86-7.91 (2H, m), 8.06 (1H, s) 416

42 3-[4-(Adamantan-2- ylcarbamoyl)-5- propylsulfanyl-pyrazol-1-ylmethyl]- benzoic acid methyl ester 1H NMR (300.072 MHz,CDCl₃) δ 0.81 (3H, t), 1.37- 1.50 (2H, m), 1.58-1.75 (4H, m), 1.82 (8H,s), 1.95 (2H, s), 2.50 (2H, t), 3.84 (3H, s), 4.20-4.23 (1H, m), 5.49(2H, s), 7.33-7.35 (2H, m), 7.83- 7.92 (3H, m), 8.09 (1H, s) 468

43 4-[4-(Adamantan-2- ylcarbamoyl)-5- propylsulfanyl-pyrazol-1-ylmethyl]- benzoic acid methyl ester 1H NMR (300.072 MHz,CDCl₃) δ 0.80 (3H, t), 1.36- 1.49 (2H, m), 1.58-1.77 (4H, m), 1.82 (8H,s), 1.95 (2H, s), 2.49 (2H, t), 3.83 (3H, s), 4.20-4.23 (1H, m), 5.50(2H, s), 7.19 (2H, d), 7.84 (1H, d), 7.92 (2H, d), 8.10 (1H, s) 468

Intermediate #441-(4-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylicacid

TFA (1.5 ml) was added to a stirred solution of1-(4-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylicacid tert-butyl ester (Intermediate #46) (274 mg, 0.70 mmol) in DCM (6ml). The reaction was stirred at ambient temperature for 3 hours thenevaporated in vacuo. The resulting gum was sonicated with isohexane toyield a solid. The solvent was removed then the white solid wasdissolved in EtOAc and evaporated in vacuo to yield the title compoundas an off white solid (236 mg, 100%).

¹H NMR (300.072 MHz, CDCl₃) δ0.84 (3H, t), 1.35-1.50 (2H, m), 2.81 (2H,t), 3.83 (3H, s), 5.53 (2H, s), 7.18-7.21 (2H, d), 7.91-7.94 (2H, d),8.05 (1H, s)

MS m/e MH⁺ 335.

Intermediate #451-(3-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylicacid

Compound prepared in an analogous manner to Intermediate 44, replacing1-(4-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylicacid tert-butyl ester with1-(3-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylicacid tert-butyl ester (Intermediate #47)

¹H NMR (300.072 MHz, CDCl₃) δ0.85 (3H, t), 1.37-1.49 (2H, m), 2.82 (2H,t), 3.83 (3H, s), 5.52 (2H, s), 7.33-7.34 (2H, m), 7.88-7.91 (2H, m),8.05 (1H, s)

MS m/e [M−H]-333.

Intermediate #461-(4-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylicacid tert-butyl ester

5-Chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester (Intermediate #48) (397 mg, 1.13 mmol) was dissolved inbutyronitrile (8 mL), potassium carbonate (470 mg, 3.40 mmol) andpropanethiol (128 μl, 1.41 mmol) were added and the mixture heated toreflux and stirred at this temperature over night. The reaction mixturewas transferred to a microwave vial (using ˜5 ml extra Butyronitrile toensure complete transfer), a further 3 eq of propane thiol was added andthe reaction was heated at 180° C. for 4 hours. EtOAc (˜50 mL) was addedand the mixture washed with water (3×˜20 mL) and brine (˜20 ml) thendried (MgSO₄), filtered and evaporated to give a yellow oil. Oilpurified by column chromatography (12 g Si, eluting with 10 to 50% EtOAcin 1H) to yield the title compound as a yellow oil (274 mg, 62%).

¹H NMR (300.072 MHz, CDCl₃) δ0.90 (3H, t), 1.40-1.52 (2H, m), 1.55 (9H,s), 2.84 (2H, t), 3.90 (3H, s), 5.57 (2H, s), 7.25 (2H, d), 7.96-8.00(3H, m)

MS m/e MH⁺ 391.

Intermediate #471-(3-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylicacid tert-butyl ester

Compound prepared in an analogous manner to Intermediate #46, replacing5-Chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester with5-Chloro-1-(3-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester

¹H NMR (300.072 MHz, CDCl₃) δ0.91 (3H, t), 1.42-1.54 (2H, m), 1.56 (9H,s), 2.84 (2H, t), 3.90 (3H, s), 5.56 (2H, s), 7.37-7.41 (2H, m),7.93-7.97 (3H, m)

MS m/e MH⁺ 391.

Intermediate #485-Chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester

t-Butylnitrite (417 μl, 3.48 mmol) and copper chloride (583 mg, 4.35mmol) were added to acetonitrile (20 mL) and heated to 65° C. A solutionof 5-Amino-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester (Intermediate #50) in acetonitrile (˜4 ml) was addeddropwise. After the addition was complete heating was continued for afurther 15 min. Cooled to ambient, diluted with water (˜100 mL) andextracted with ethyl acetate (3×˜40 mL). The combined extracts werewashed with water (2×˜20 mL) and brine (˜20 mL), dried (MgSO4), filteredand evaporated to an oil. Chromatographed (40 g silica column,EtOAc/Hexane 10-50%) to yield the title compound to as an off whitesolid (397 mg, 39%).

¹H NMR (300.072 MHz, CDCl₃) δ1.49 (9H, s), 3.83 (3H, s), 5.33 (2H, s),7.19 (2H, d), 7.84 (1H, s), 7.93 (2H, d)

MS m/e [M+Na]⁺ 373.

Intermediate #495-Chloro-1-(3-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester

Compound prepared in an analogous manner to Intermediate #48, replacing5-Amino-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester with5-Amino-1-(3-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester (Intermediate #51)

¹H NMR (300.072 MHz, CDCl₃) δ1.49 (9H, s), 3.84 (3H, s), 5.32 (2H, s),7.33-7.35 (2H, m), 7.84 (1H, s), 7.88-7.93 (2H, m)

MS m/e [M−^(t)Bu+H]⁺ 295.

Intermediate #505-Amino-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester

t-Butyl cyanoacetate (600 mg, 4.25 mmol) was dissolved in triethylorthoformate (1.06 ml, 6.38 mmol), acetic anhydride (0.40 ml, 4.25 mmol)was added and the mixture heated to 125° C. for 2 hours. The solutionwas evaporated to leave a yellow oil. This oil was redissolved inethanol (5 ml) and treated with 4-Hydrazinomethyl-benzoic acid methyl toester hydrochloride (Intermediate #52) (230 mg, 1.06 mmol) and DIPEA(184 μl, 1.06 mmol). The resulting mixture was heated to reflux for 2 hand then cooled to ambient temperature and evaporated to leave a brownoil. This oil was dissolved in ethyl acetate (50 mL), washed with water(2×20 mL) and brine (20 mL) then dried (MgSO4), filtered and evaporated.The residue was chromatographed (40 g silica EtOAc/Hexane 0-50%) toyield the title compound as a yellow solid (214 mg, 43%).

¹H NMR (300.072 MHz, CDCl₃) δ1.55 (9H, s), 3.90 (3H, s), 4.86 (2H, s),5.18 (2H, s), 7.21 (2H, d), 7.62 (1H, s), 8.00 (2H, d)

MS m/e [M−H]⁻ 330.

Intermediate #515-Amino-1-(3-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acidtert-butyl ester

Compound prepared in an analogous manner to Intermediate #50, replacing4-Hydrazinomethyl-benzoic acid methyl ester hydrochloride with3-Hydrazinomethyl-benzoic acid methyl ester hydrochloride (Intermediate#53)

¹H NMR (300.072 MHz, CDCl₃) δ1.47 (9H, s), 3.84 (3H, s), 4.75 (2H, s),5.11 (2H, s), 7.26 (1H, d), 7.36 (1H, t), 7.55 (1H, s), 7.83 (1H, s),7.90 (1H, d)

MS m/e MH³³².

Intermediate #52 4-Hydrazinomethyl-benzoic acid methyl esterhydrochloride

A solution of methyl4-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoate(Intermediate #54) (3.3 g, 8.67 mmol) in 4M to HCl in Dioxane (100 mL)was stirred overnight at ambient temperature. The solvent was removedunder reduced pressure and the resulting solid was dissolved in hotMeOH. The hot suspension was filtered then evaporated in vacuo to give asolid. This solid was triturated with ether, filtered then dried underhigh vac to yield the title compound as a yellow solid (1.5 g, 80%).

¹H NMR (300.073 MHz, DMSO-d₆) δ3.85 (3H, s), 4.13 (2H, s), 7.55 (2H, d),7.93 (2H, d)

Intermediate #53 3-Hydrazinomethyl-benzoic acid methyl esterhydrochloride

Compound prepared in an analogous manner to intermediate #52, replacing4-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoatewith3-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoate(Intermediate #55)

¹H NMR (300.073 MHz, DMSO-d₆) δ3.86 (3H, s), 4.13 (2H, s), 7.52 (1H, t),7.70 (1H, d), 7.91 (1H, d), 8.02 (1H, s), 8.77 (4H, br s)

MS m/e MH⁺ 181.

Intermediate #54 methyl4-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoate

NaH (362 mg, 9.04 mmol) was added to a stirred solution of Di-Tert-ButylHydrazodicarboxylate (2 g, 8.61 mmol) in anhydrous THF (50 ml). Thereaction was stirred at ambient temperature for 10 minutes then treatedwith a solution of Methy 4-(Bromomethyl)Benzoate (1.98 g, 8.61 mmol) inanhydrous THF (20 ml). The reaction was stirred at ambient temperaturefor 4 hours. The reaction was partitioned between ether (˜100 ml) andwater (˜100 ml). The layers were separated and the aqueous layer wasre-extracted with ether (˜50 ml). The ether layers were combined, washedwith brine (˜50 ml), dried (MgSO₄), filtered and evaporated to yield thetitle compound (3.3 g, 100%).

¹H NMR (300.073 MHz, DMSO-d₆) 6.1.38 (18H, s), 3.84 (3H, s), 4.52 (2H,br s), 7.42 (2H, d), 7.90 (2H, d), 9.19 (1H, s)

MS m/e [M+Na]⁺ 403.

Intermediate #55 methyl3-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoate

Compound prepared in an analogous manner to Intermediate #54, replacingMethyl 4-(Bromomethyl)Benzoate with Methyl 3-(Bromomethyl)Benzoate

¹H NMR (400.13 MHz, DMSO-d₆) δ1.39 (18H, s), 3.86 (3H, s), 4.50-4.58(2H, m), 7.45-7.52 (1H, m), 7.57 (1H, d), 7.85-7.90 (2H, m), 9.25 (1H,s)

MS m/e [M+Na]⁺ 403.

Intermediate #56 methyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoate

Methyl 4-hydrazinylbenzoate hydrochloride (Intermediate #123) (3.04 g,15.00 mmol) was added in one portion to(2)-N-(2-adamantyl)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanamide(Intermediate #58) (4.99 g, 15 mmol) in ethanol (100 mL). 5 drops ofacetic acid were added and the resulting solution was stirred at 80° C.for 2 hours. The reaction mixture was concentrated and diluted withEtOAc (500 mL), and washed sequentially with water (200 mL), andsaturated brine (200 mL). The organic layer was dried over MgSO4,filtered and evaporated to afford crude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to afford methyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoate (4.66 g,71.3%) as a yellow solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.19 (9H, s), 1.50 (2H, d), 1.69-1.95(10H, m), 2.09 (2H, d), 3.91 (3H, s), 3.99 (1H, d), 7.53-7.56 (2H, m),7.62 (1H, s), 8.09-8.12 (2H, m), 8.20 (1H, d)

m/z (ESI+) (M+H)+=436

Intermediate #56 may also be prepared as follows:

2-(4-(Methoxycarbonyl)phenyl)hydrazinium chloride (Intermediate #123) (1equiv.) and then acetic acid (0.023 equivs.) were added to a solution of(2Z)—N-(2-adamantyl)-2-(dimethylamino-methylidene)-4,4-dimethyl-3-oxo-pentanamide(Intermediate #58) (1 equiv.) in methanol (200 vols.), under nitrogen.The mixture stirred under reflux for 1.5 hours, cooled, concentrated tobelow 3.5 vols. and the resulting suspension diluted with ethyl acetate(96 vols.). The suspension was washed with water (34.4 vols.) giving asolution which was washed with brine (34.4 vols.), dried (MgSO₄) andconcentrated to dryness. The crude product was slurried in MTBE (9vols.) and stirred for 15 minutes. The pale yellow solid was filtered,washed with MTBE (11.4 vols.) and dried under vacuum at 60 C.

TLC DCM:MeOH, 9:1, Product R_(f) 0.86 (trace impurity R_(f) 0.68)

mp 193.6-194.5 C

Intermediate #57 methyl4-[4-(2-adamantylcarbamoyl)-5-(1-methylcyclopropyl)pyrazol-1-yl]benzoate

Methyl 4-hydrazinylbenzoate hydrochloride (Intermediate #123) (0.809 g,3.99 mmol) was added in one portion to(Z)—N-(2-adamantyl)-3-dimethylamino-2-(1-methylcyclopropanecarbonyl)prop-2-enamide(Intermediate #59), 1.320 g, 3.99 mmol) in ethanol (30 mL). 5 drops ofacetic acid were added and the resulting solution was stirred at 80° C.for 2 hours. The reaction mixture was concentrated and diluted withEtOAc (100 mL), and washed sequentially with water (50 mL), andsaturated brine (50 mL). The organic layer was dried over MgSO4,filtered and evaporated to afford crude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to afford methyl4-[4-(2-adamantylcarbamoyl)-5-(1-methylcyclopropyl)pyrazol-1-yl]benzoate(1.221 g, 70.5%) as a cream solid.

m/z (ESI+) (M+H)+=434; HPLC t_(R)=2.98 min.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.48-0.51 (2H, m), 0.67-0.69 (2H, m),1.54-1.57 (5H, m), 1.73 (2H, s), 1.83-1.86 (6H, m), 1.97 (2H, s),2.04-2.07 (2H, m), 3.90 (3H, s), 4.05-4.10 (1H, m), 7.50 (1H, d), 7.71(2H, d), 8.09 (1H, s), 8.13 (2H, d)

Intermediate #58(2)-N-(2-adamantyl)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanamide

N,N-Dimethylformamide dimethyl acetal (3.02 mL, 22.71 mmol) was added toa stirred suspension of N-(2-adamantyl)-4,4-dimethyl-3-oxo-pentanamide(Intermediate #60) (5.25 g, 18.93 mmol) in 1,4-dioxane (50 mL) undernitrogen. The resulting mixture was stirred at 100° C. for 2 hours. Thereaction mixture was evaporated to dryness and the resulting pale creamsolid was dried under vacuum to afford(2)-N-(2-adamantyl)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanamide(5.83 g, 93%).

1H NMR (400.13 MHz, DMSO-d₆) δ 1.13 (9H, s), 1.47 (2H, d), 1.69-1.83(10H, m), 2.03 (2H, d), 2.92 (6H, s), 3.90 (1H, d), 7.24 (1H, s), 7.94(1H, d)

m/z (ESI+) (M+H)+=333

Intermediate #58 may also be prepared as follows:

N,N-Dimethylformamide dimethyl acetal (1.2 equivs.) was added to asolution of N-(2-adamantyl)-4,4-dimethyl-3-oxo-pentanamide (Intermediate#60) (1 equiv.) in 1,4-dioxane (9.6 vols.) under nitrogen. The mixturewas heated under reflux for five hours and then cooled to roomtemperature. The solvent was removed in vacuo and the pale yellow solidused directly in the next stage.

TLC Hexane:EtOAc, 1:1, Product R_(f) 0.94 (impurities: R_(f) 0.06+0.66)

mp 143.6-147.6 C

Intermediate #59(Z)—N-(2-adamantyl)-3-dimethylamino-2-(1-methylcyclopropanecarbonyl)prop-2-enamide

Prepared from N-(2-adamantyl)-3-(1-methylcyclopropyl)-3-oxo-propanamide(Intermediate #61) by the same process as used for Intermediate #58

1H NMR (400.13 MHz, DMSO-d₆) δ 0.54-0.55 (2H, m), 0.91-0.94 (2H, m),1.26 (3H, s), 1.51 (2H, d), 1.69 (2H, s), 1.72-1.85 (8H, m), 1.92 (2H,d), 3.00 (6H, s), 3.90-3.92 (1H, m), 7.57 (1H, s), 8.08 (1H, s)

Intermediate #60 N-(2-adamantyl)-4,4-dimethyl-3-oxo-pentanamide

A 1M solution of solution of lithium bis(trimethylsilyl)amide in THF(22.84 ml, 22.84 mmol) was added to THF (25 mL) and cooled undernitrogen to −78° C. A solution of 3,3-dimethyl-2-butanone (2.287 g,22.84 mmol) in THF (25 mL) was added drop wise over a period of 5minutes. The resulting solution was stirred at −78° C. under nitrogenfor minutes. A solution of 2-isocyanatoadamantane (prepared from2-adamantylamine hydrochloride by the method of R. Reck & C. JochimsChem. Ber. 115 (1982) p 864) (3.68 g, 20.76 mmol) in THF (20 mL) wasadded over a period of 5 minutes. The resulting solution was stirred at−78° C. for 1 hour and then allowed to warm to 20° C. over 1 h. Thereaction mixture was poured into saturated NH₄Cl (150 mL) and extractedwith EtOAc (2×100 mL), the organic layer was washed with water (50 mL)and brine (50 mL) dried over MgSO4, filtered and evaporated to afford ayellow oil. The crude product was purified by flash silicachromatography, elution gradient 0 to 50% EtOAc in isohexane. Purefractions were evaporated to dryness to affordN-(2-adamantyl)-4,4-dimethyl-3-oxo-pentanamide (4.64 g, 81%) as a whitesolid.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.08-1.09 (9H, m), 1.50 (2H, d),1.66-1.89 (10H, m), 1.95-2.00 (2H, m), 3.53 (1.4H, s), 3.80-3.94 (1H,m), 5.30 (0.3H, s), 7.77-7.87 (1H, m), 14.43 (0.3H, s) (2:1 mixture ofketo and enol forms)

m/z (ESI+) (M+H)+=278

Intermediate #60 may also be prepared as follows:

Aqueous sodium hydroxide solution (3M) (5 vols.) was added to a stirredsuspension of 2-adamantylamine hydrochloride (1 equiv.) in water (5vols.). DCM (5 vols.) was added to to the resulting thick suspension andthe phases separated. The aqueous was extracted with DCM (4×5 vols.) andthe combined organics concentrated to give the free amine as a whitesolid.

Ethyl pivaloylacetate (1 equiv.) was added to a suspension of the freeamine in xylenes (6.5 vols.), under nitrogen, and the mixture stirredunder reflux for 6.5 hours. The batch was cooled to room temperature andconcentrated to dryness. The residue was purged with toluene (3×1 vol.)followed by hexane (3×1 vol.). The resulting solid was digested inhexane at 50° C. for five minutes and then cooled to room temperature.The white solid was filtered, washed with hexane (2 vols.) and dried inair.

TLC Hexane:EtOAc, 1:1, Product R_(f) 0.66

mp 124.5-125.1 C

Intermediate #61N-(2-adamantyl)-3-(1-methylcyclopropyl)-3-oxo-propanamide

Prepared from 1-(1-methylcyclopropyl)ethanone by the same process asused for Intermediate #60

m/z (ESI+) (M+H)+=276; HPLC t_(R)=2.26 min.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.76-0.78 (2H, m), 1.18-1.20 (2H, m),1.25 (3H, s), 1.50 (2H, d), 1.70-1.80 (11H, m), 1.95 (2H, d), 3.82 (1H,d), 7.83 (1H, d)

Intermediate #62 methyl4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoate

Methyl 4-hydrazinylbenzoate hydrochloride (Intermediate #123) (0.712 g,3.51 mmol) was added in one portion to(Z)—N-(2-adamantyl)-2-(cyclopentanecarbonyl)-3-dimethylamino-prop-2-enamide(Intermediate #67), 1.21 g, 3.51 mmol) in ethanol (30 mL). 5 drops ofacetic acid were added and the resulting solution was stirred at 80° C.for 2 hours and then cooled to ambient giving a precipitate. Thereaction mixture was filtered and the product recovered, washed withethanol (10 mL) and water (10 mL) before being dried under vacuum togive methyl4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoate (0.620g, 39.4%) as a white solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.48-1.53 (4H, m), 1.71-1.85 (12H, m),1.94 (2H, s), 2.02-2.12 (4H, m), 2.98-3.09 (1H, m), 3.90 (3H, s),3.98-4.03 (1H, m), 7.57-7.60 (2H, m), 7.74-7.76 (1H, m), 8.10-8.15 (3H,m)

m/z (ESI+) (M+H)+=448; HPLC t_(R)=3.26 min.

The same process as used for Intermediate #62 prepared the followingintermediates from the appropriate starting material.

MS m/e Structure Int # Name ¹H NMR δ MH⁺

63 methyl 4-[4- (2-adamantyl- carbamoyl)-5- ethylpyrazol- 1-yl]benzoate1H NMR (400.13 MHz, DMSO-d₆) δ 1.03 (3H, t), 1.53 (2H, d), 1.72 (2H, s),1.84 (6H, d), 1.95 (2H, s), 2.11 (2H, d), 2.98 (2H, q), 3.90 (3H, s),4.04 (1H, t), 7.59-7.61 (1H, m), 7.65-7.68 (2H, m), 8.12- 8.15 (2H, m),8.30 (1H, s) 408

64 methyl 4-[4- (2-adamantyl- carbamoyl)-5- propan-2- ylpyrazol-1-yl]benzoate H NMR (400.13 MHz, DMSO-d₆) δ 1.30 (6H, d), 1.52 (2H, d),1.73 (2H, s), 1.82-1.86 (6H, m), 1.97 (2H, s), 2.11 (2H, d), 3.11-3.18(1H, m), 3.91 (3H, s), 4.00-4.05 (1H, m), 7.57 (2H, d), 7.67 (1H, d),8.08 (1H, s), 8.13 (2H, d) 422

65 methyl 4-[4- (2-adamantyl- carbamoyl)-5- cyclobutyl- pyrazol-1-yl]benzoate 1H NMR (400.13 MHz, DMSO-d₆) δ 1.51-1.54 (2H, m), 1.65 (1H,q), 1.72 (2H, s), 1.76- 1.85 (7H, m), 1.96 (2H, s), 2.04- 2.15 (4H, m),2.18-2.26 (2H, m), 3.82 (1H, q), 3.90 (3H, s), 4.00- 4.06 (1H, m), 7.59(2H, d), 7.81 (1H, d), 7.95 (1H, s), 8.11 (2H, d) 434

Intermediate #66N-(2-adamantyl)-1-(4-cyanophenyl)-5-methyl-pyrazole-4-carboxamide

Acetic acid (0.031 mL, 0.50 mmol) was added in one portion to(2E)-N-(2-adamantyl)-2-(dimethylaminomethylidene)-3-oxo-butanamide(Intermediate #71)(1.45 g, 4.99 mmol) and 4-cyanophenylhydrazinehydrochloride (0.847 g, 4.99 mmol) in ethanol (40 mL). The resultingsuspension was stirred at 80° C. for 3 hours. The reaction mixture wasconcentrated and diluted with EtOAc (75 mL), and washed sequentiallywith water (50 mL) and saturated brine (50 mL). The organic layer wasdried over MgSO4, filtered and evaporated to afford crude product.

The crude product was purified by flash silica chromatography, elutiongradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to affordN-(2-adamantyl)-1-(4-cyanophenyl)-5-methyl-pyrazole-4-carboxamide (1.3g, 72%) as an orange solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.45-1.58 (2H, m), 1.70-1.9 (8H, m),1.92-1.99 (2H, m), 2.05-2.15 (2H, m), 2.57 (3H, s), 4.00-4.06 (1H, m),7.59 (1H, d), 7.79 (2H, d), 8.05 (2H, d), 8.32 (1H, s)

m/z (ESI+) (M+H)+=361;

Intermediate #67(Z)—N-(2-adamantyl)-2-(cyclopentanecarbonyl)-3-dimethylamino-prop-2-enamide

N,N-Dimethylformamide dimethyl acetal (0.587 mL, 4.42 mmol) was added toN-(2-adamantyl)-3-cyclopentyl-3-oxo-propanamide (Intermediate #72),(1.023 g, 3.53 mmol) in 1,4-dioxane (25 mL). The resulting solution wasstirred at 100° C. for 2 hours. The resulting mixture was evaporated todryness to afford(Z)—N-(2-adamantyl)-2-(cyclopentanecarbonyl)-3-dimethylamino-prop-2-enamide(1.210 g, 99%).

1H NMR (400.13 MHz, DMSO-d₆) δ 1.45-1.50 (4H, m), 1.54-1.68 (8H, m),1.72-1.85 (8H, m), 2.00 (2H, d), 2.97 (6H, s), 3.05-3.15 (1H, m), 3.95(1H, d), 7.42 (1H, s), 8.30 (1H, d)

The same process as used for Intermediate #67 prepared the followingintermediates from the appropriate starting material.

MS m/e Structure Int # Name ¹H NMR δ MH⁺

68 (2Z)-N-(2-adamantyl)-2- (dimethylaminomethylidene)- 3-oxopentanamide1H NMR (300.073 MHz, DMSO-d₆) δ 0.94 (3H, t), 1.48 (2H, d), 1.68 (2H,s), 1.77-1.81 (8H, m), 1.95-2.00 (2H, m), 2.38 (2H, q), 2.97 (6H, s),3.92 (1H, d), 7.40 (1H, s), 8.25 (1H, d) 305

69 (2Z)-N-(2-adamantyl)-2- (dimethylaminomethylidene)-4-methyl-3-oxopentanamide 1H NMR (400.13 MHz, DMSO-d₆) δ 0.95-1.00 (6H,m), 1.50 (2H, d), 1.70 (2H, s), 1.76-1.78 (4H, m), 1.79 (2H, s), 1.82(3H, s), 2.01 (2H, d), 2.93-2.99 (6H, m), 3.58 (3H, s), 3.95 (1H, d),7.40 (1H, s), 8.24 (1H, d)

70 (Z)-N-(2-adamantyl)-2- (cyclobutanecarbonyl)-3- dimethylaminoprop-2-enamide 1H NMR (400.13 MHz, DMSO-d₆) δ 1.51 (2H, d), 1.67-1.71 (2H, m),1.78-1.87 (8H, m), 1.94-2.00 (4H, m), 2.11-2.21 (2H, m), 2.98 (5H, s),3.29 (3H, s), 3.53 (1H, t), 3.93 (1H, d), 7.37 (1H, s), 8.29 (1H, d)

71 (2Z)-N-(2-adamantyl)-2- (dimethylaminomethylidene)- 3-oxo-butanamide1H NMR (400.13 MHz, DMSO-d₆) δ 1.46-1.52 (2H, m), 1.65-1.70 (2H, m),1.72- 1.85 (8H, m), 1.92-2.00 (2H, m), 2.04 (3H, s), 2.99 (6H, s),3.91-3.96 (1H, m), 7.44 (1H, s), 8.35 (1H, d)

Intermediate #72 N-(2-adamantyl)-3-cyclopentyl-3-oxo-propanamide

2-Adamantanamine hydrochloride (1.641 g, 8.74 mmol) was added to5-(cyclopentanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione(Intermediate #77), (2.1 g, 8.74 mmol) and N-Ethyldiisopropylamine(1.512 mL, 8.74 mmol) in toluene (30 mL). The resulting suspension wasstirred at 110° C. for 2 hours. The reaction mixture was diluted withEtOAc (100 mL), and washed sequentially with 2M HCl (20 mL), and water(2×50 mL). The organic layer was dried over MgSO4, filtered andevaporated to afford crude product. The crude product was purified byflash silica chromatography, elution gradient 0 to 100% EtOAc inisohexane. Pure fractions were evaporated to dryness to affordN-(2-adamantyl)-3-cyclopentyl-3-oxo-propanamide (1.030 g, 40.7%) as abrown oil which crystallised on standing.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.46-1.59 (7H, m), 1.60-1.78 (16H, m),1.90-2.00 (2H, m), 2.95-3.03 (1H, m), 3.84 (0.9H, d), 3.90 (0.1H, d),7.78 (0.1H, d), 7.93 (0.9H, d), 14.21 (0.1H, s) 9:1 ketone:enol form

The same process as used for Intermediate #72 prepared the followingintermediates from the appropriate starting material.

Structure Int # Name ¹H NMR δ

73 N-(2- adamantyl)-3- oxopentan- amide 1H NMR (400.13 MHz, CDCl₃) δ1.11 (3H, t), 1.67 (2H, d), 1.77 (2H, s), 1.80-1.98 (10H, d), 2.59 (2H,q), 3.46 (2H, s), 4.08- 4.10 (1H, m), 7.70 (1H, s)

74 N-(2- adamantyl)-4- methyl-3- oxopentan- amide 1H NMR (400.13 MHz,DMSO-d₆) δ 0.98-1.06 (6H, m), 1.48-1.54 (2H, m), 1.70-1.73 (3H, m),1.75-1.81 (4H, m), 1.79 (4H, d), 1.95-2.00 (2H, m), 2.68-2.75 (1H, m),3.46 (1H, s), 3.84 (1H, d), 7.87 (1H, d)

75 N-(2- adamantyl)-3- cyclobutyl-3- oxopropan- amide 1H NMR (400.13MHz, DMSO-d₆) δ 1.50-1.53 (3H, m), 1.65-1.73 (3H, m), 1.74-1.81 (8H, m),1.86-1.98 (4H, m), 2.02-2.10 (4H, m), 3.29 (1H, s), 3.84 (1H, d), 7.88(1H, d)

76 N-(2- adamantyl)-3- oxo-butan- amide 1H NMR (400.13 MHz, DMSO-d₆) δ1.48-1.54 (2H, m), 1.69-1.85 (10H, m), 1.92- 2.00 (2H, s), 2.13 (3H, s),3.38 (2H, s), 3.84 (1H, d), 7.95 (1H, d)

Intermediate #775-(cyclopentanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

A solution of cyclopentanecarbonyl chloride (1.100 mL, 9.05 mmol) in DCM(5 mL) was added dropwise to a stirred solution of isopropylidenemalonate (1.304 g, 9.05 mmol), and pyridine (1.464 mL, 18.10 mmol) inDCM (20 mL) at 5° C., over a period of 10 minutes under nitrogen. Theresulting solution was stirred at 5° C. for 1 hour and then allowed towarm to 20° C. and stirred for another hour. The reaction mixture wasdiluted with DCM (100 mL), and washed sequentially with 2M HCl (2×50mL), water (50 mL), and saturated brine (50 mL). The organic layer wasdried over MgSO4, filtered and evaporated to afford crude product,5-(cyclopentanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.100 g,97%) as a brown oil.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.51-1.60 (5H, m), 1.61-1.68 (3H, s),1.70-1.79 (4H, m), 1.84-1.98 (2H, m), 2.89-3.00 (1H, m), 4.04 (1H, s

The same process as used for Intermediate #77 prepared the followingintermediates from to the appropriate starting materials.

Structure Int # Name ¹H NMR δ

78 2,2-dimethyl-5- propanoyl-1,3- dioxane-4,6-dione Used crude

79 2,2-dimethyl-5-(2- methylpropanoyl)- 1,3-dioxane-4,6- dione 1H NMR(400.13 MHz, DMSO-d₆) δ 1.02-1.08 (1H, m), 1.15-1.18 (6H, m), 1.70-1.72(6H, m), 3.92-3.99 (1H, m)

80 5- (cyclobutane- carbonyl)-2,2- dimethyl-1,3- dioxane-4,6-dione 1HNMR (400.13 MHz, DMSO-d₆) δ 1.68 (6H, s), 1.82- 1.89 (2H, m), 2.09 (2H,s), 2.05-2.13 (2H, m), 2.18-2.32 (5H, m), 4.30-4.35 (1H, m)

81 5-acetyl-2,2- dimethyl-1,3- dioxane-4,6-dione Used crude

Intermediate #821-(4-bromophenyl)-5-tert-butyl-N-cyclohexyl-1H-pyrazole-4-carboxamide

Ethyl (2)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanoate(Intermediate #83) (1.24 g, 5.88 mmol) was dissolved in ethanol (20 mL).4-bromophenylhydrazine HCl (1.32 g, 5.88 mmol) and DIPEA (1.02 mL, 5.88mmol) were added. The mixture was heated to reflux for 2 h cooled toambient and evaporated under reduced pressure. The residue was dissolvedin DCM (50 mL), washed with water (2×10 mL), dried (MgSO4) andevaporated to afford crude product. The crude product was purified byflash silica chromatography, elution gradient 0 to 25% EtOAc inisohexane. Pure fractions were evaporated to dryness to afford1-(4-bromophenyl)-5-tert-butyl-N-cyclohexyl-1H-pyrazole-4-carboxamide(627 mg, 32%)

1H NMR (300.073 MHz, DMSO-d₆) δ 1.23 (9H, s), 1.29 (3H, t), 4.24 (2H,q), 7.39-7.41 (2H, m), 7.69-7.72 (2H, m), 7.92 (1H, s)

m/z (ESI+) (M+H)+=353

Intermediate #83 Ethyl(2)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanoate

Ethyl pivaloylacetate (1.72 g, 10 mmol) and N,N-dimethylformamidedimethylacetal (1.68 mL, 12.5 mmol) were dissolved in dioxan (20 mL) andheated to reflux for 3 h. The reaction mixture was cooled to ambient andevaporated under reduced pressure to leave crude product. The crudeproduct was purified by flash chromatography on silica gel (elutiongradient 0 to 100% EtOAc in hexane) to afford Ethyl(2)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanoate as acolourless oil that crystallised on standing. (1.24 g, 54%)

1H NMR (300.073 MHz, DMSO-d₆) δ 1.11 (9H, d), 1.18 (3H, t), 2.82 (6H,s), 4.04 (2H, q), 7.31 (1H, s)

m/z (ESI+) (M+H)+=228

Intermediate #84 methyl4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoate

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191 mg,1.00 mmol) was added in one portion to5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid (Intermediate #88) (300 mg, 0.83 mmol), 2-Adamantanaminehydrochloride (172 mg, 0.92 mmol) and N-Ethyldiisopropylamine (0.432 mL,2.50 mmol) in DMF (7 mL) at 20° C. under nitrogen. The resulting mixturewas stirred at 20° C. for 18 hours.

The reaction mixture was diluted with EtOAc (75 mL), and washedsequentially with water (4×25 mL) and saturated brine (25 mL). Theorganic layer was dried over MgSO4, filtered and evaporated to affordcrude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 50% EtOAc in isohexane. Purefractions were evaporated to dryness to afford methyl4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoate(349 mg, 85%) as a white crystalline solid.

1H NMR (300.073 MHz, DMSO-d6) δ 1.05 (5H, d), 1.39-1.54 (5H, m), 1.62(2H, d), 1.73 (2H, s), 1.83 (6H, s), 1.94-2.01 (4H, m), 2.92 (1H, s),3.89 (3H, s), 4.09 (1H, d), 7.76 (2H, d), 8.04 (1H, d), 8.12 (2H, d),8.17 (1H, s)

m/z (ESI+) (M+H)+=494

The following Intermediates were prepared in a similar manner toIntermediate #84 from5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid (Intermediate #88) and an appropriate amine.

MS m/e Structure Int. # Name ¹H NMR δ MH⁺

85 methyl 4-[4-(1- adamantylcarbamoyl)-5- cyclohexylsulfanyl-pyrazol-1-yl]benzoate 1H NMR (400.13 MHz, DMSO-d6) δ 1.05-1.17 (5H, m), 1.42 (1H,s), 1.51-1.63 (4H, m), 1.68 (6H, s), 2.02-2.12 (9H, m), 2.98 (1H, s),3.91 (3H, s), 7.53 (1H, s), 7.72-7.74 (2H, m), 8.13 (3H, d) (ESI+) 494

86 methyl 4-[5- cyclohexylsulfanyl-4- [[(1S,3R)-5-hydroxy-2-adamantyl]carbamoyl]pyrazol- 1-yl]benzoate 1H NMR (400.13 MHz, DMSO-d6)δ 1.02-1.10 (5H, m), 1.41-1.56 (7H, m), 1.67 (4H, d), 1.76 (2H, d), 1.89(2H, d), 2.08 (3H, s), 2.93 (1H, s), 3.91 (3H, s), 4.03 (1H, d), 4.43(1H, s), 7.76-7.79 (2H, m), 7.97 (1H, d), 8.13-8.15 (2H, m), 8.18 (1H,s) (ESI+) 510

87 methyl 4-[5- cyclohexylsulfanyl-4-[[5- (difluoromethoxy)-2-adamantyl]carbamoyl]pyrazol- 1-yl]benzoate 1H NMR (400.13 MHz, DMSO-d6)δ 1.00-1.10 (5H, m), 1.41 (1H, s), 1.45-1.58 (6H, m), 1.91- 1.99 (6H,m), 2.05 (2H, d), 2.18 (3H, d), 2.95 (1H, d), 3.91 (3H, s), 4.10 (1H,t), 6.88 (1H, t), 7.75-7.79 (2H, m), 7.99 (1H, d), 8.12-8.16 (2H, m),8.19 (1H, s) (ESI+) 560

Intermediate #885-cyclohexylsulfanyl-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylicacid

Trifluoroacetic acid (4.72 mL, 61.46 mmol) was added to tert-butyl5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #89) (2.56 g, 6.15 mmol) in CH₂Cl₂ (40 mL) The resultingsolution was stirred at 20° C. for 24 hours. The reaction mixture wasevaporated to dryness, re-dissolved in dioxan (20 mL) and re-evaporatedto dryness to afford5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid (2.25 g, 100%) as a white crystalline solid.

1H NMR (400.13 MHz, DMSO-d6) δ 1.04-1.11 (5H, m), 1.42 (1H, s), 1.51(2H, s), 1.59 (2H, d), 3.31-3.22 (1H, m), 3.91 (3H, s), 7.70-7.73 (2H,m), 8.11-8.15 (2H, m), 8.19 (1H, s), 12.66 (1H, s)

MS m/z (ESI+) (M+H)+=361.

Intermediate #89 tert-butyl5-cyclohexylsulfanyl-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate

Sodium bis(trimethylsilyl)amide (10.69 mL, 10.69 mmol) was addeddropwise to Cyclohexanethiol (1.307 mL, 10.69 mmol) in DMF (35 mL) undernitrogen. The resulting solution was stirred at 20° C. for 30 minutes. Asolution of tert-butyl5-chloro-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #9) (3 g, 8.91 mmol) in DMF (10 mL) was then addeddropwise and the resulting mixture was stirred at 20° C. for 2 hours.

The reaction mixture was diluted with EtOAc (200 mL), and washedsequentially with water (4×50 mL) and saturated brine (50 mL). Theorganic layer was dried over to MgSO4, filtered and evaporated to affordcrude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated todryness to afford tert-butyl

5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(2.56 g, 69.0%) as a colourless oil which crystallised on standing.

1H NMR (400.13 MHz, DMSO-d6) δ 0.95-1.05 (5H, m), 1.35 (1H, s),1.42-1.55 (13H, d), 3.12 (1H, d), 3.81 (3H, s), 7.69-7.72 (2H, m),8.11-8.14 (2H, m), 8.16 (1H, s)

m/z (ESI+) (M+H)+=417

Intermediate #90 methyl4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (199 mg,1.04 mmol) was added in one portion to5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid (Intermediate #93) (300 mg, 0.87 mmol), 2-Adamantanaminehydrochloride (179 mg, 0.95 mmol), 1-Hydroxybenzotriazole (140 mg, 1.04mmol) and N-Ethyldiisopropylamine (0.450 mL, 2.60 mmol) in DMF (7 mL) at20° C. under nitrogen. The resulting mixture was stirred at 20° C. for18 hours.

The reaction mixture was diluted with EtOAc (75 mL), and washedsequentially with water (4×25 mL) and saturated brine (25 mL). Theorganic layer was dried over MgSO4, filtered to and evaporated to affordcrude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to afford methyl4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate(336 mg, 81%) as a white crystalline solid.

1H NMR (400.13 MHz, DMSO-d6) δ 1.17-1.25 (2H, m), 1.35-1.42 (4H, m),1.65 (4H, d), 1.74 (2H, s), 1.87 (6H, d), 1.96-2.02 (4H, m), 3.25-3.35(1H, m), 3.91 (3H, s), 4.12 (1H, t), 7.78-7.82 (2H, m), 8.08 (1H, d),8.13-8.16 (2H, m), 8.19 (1H, s)

m/z (ESI+) (M+H)+=480 m/z (ESI+) (M+H)+=480

The following Intermediates were prepared in a similar manner toIntermediate #90 from5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid (Intermediate #93) and an appropriate amine.

MS m/e Structure Int # Name ¹H NMR δ (M + H)+

91 methyl 4-[4-(1- adamantylcarbamoyl)-5- cyclopentylsulfanyl-pyrazol-1-yl]benzoate 1H NMR (400.13 MHz, DMSO-d6) δ 1.19-1.27 (2H, m), 1.40-1.48(4H, m), 1.63-1.71 (8H, m), 2.07 (9H, s), 3.31- 3.37 (1H, m), 3.91 (3H,s), 7.54 (1H, s), 7.74-7.77 (2H, m), 8.12-8.15 (3H, m) 480

92 methyl 4-[5- cyclopentylsulfanyl-4- [[(1S,3R)-5-hydroxy-2-adamantyl]carbamoyl]pyrazol- 1-yl]benzoate 1H NMR (400.13 MHz, DMSO-d6)δ 1.17-1.24 (2H, m), 1.32-1.48 (6H, m), 1.64 (6H, d), 1.76 (2H, d), 1.89(2H, d), 2.08 (3H, s), 3.25- 3.35 (1H, m), 3.91 (3H, s), 4.03 (1H, t),4.41 (1H, s), 7.77- 7.81 (2H, m), 7.98 (1H, d), 8.13-8.17 (2H, m), 8.19(1H, s) 496

Intermediate #935-cyclopentylsulfanyl-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylicacid

Trifluoroacetic acid (2.63 mL, 34.29 mmol) was added to tert-butyl5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #94) (1.38 g, 3.43 mmol) in CH₂Cl₂ (25 mL) The resultingsolution was stirred at 20° C. for 24 hours. The reaction mixture wasevaporated to dryness, re-dissolved in dioxan (20 mL) and re-evaporatedto dryness to afford5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid (1.180 g, 99%) as a white to crystalline solid.

1H NMR (400.13 MHz, DMSO-d6) δ 1.20-1.26 (2H, m), 1.37-1.47 (4H, m),1.65-1.73 (2H, m), 3.65-3.71 (1H, m), 3.86-3.96 (3H, m), 7.68-7.76 (2H,m), 8.11-8.15 (2H, m), 8.19 (1H, s), 12.84 (1H, s)

MS m/z (ESI−) (M−H)−=345

Intermediate #94 tert-butyl5-cyclopentylsulfanyl-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate

Sodium bis(trimethylsilyl)amide (7.13 mL, 7.13 mmol) was added dropwiseto cyclopentanethiol (0.761 mL, 7.13 mmol) in DMF (25 mL) undernitrogen. The resulting solution was stirred at 20° C. for 30 minutes. Asolution of tert-butyl5-chloro-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #9) (2 g, 5.94 mmol) in DMF (10 mL) was then addeddropwise and the resulting mixture was stirred at 20° C. for to 2 hours.The reaction mixture was diluted with EtOAc (200 mL), and washedsequentially with water (4×50 mL) and saturated brine (50 mL). Theorganic layer was dried over MgSO4, filtered and evaporated to affordcrude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 25% EtOAc in isohexane. Purefractions were evaporated to dryness to afford tert-butyl5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(1.380 g, 57.7%) as a colourless oil which crystallised on standing.

1H NMR (300.073 MHz, DMSO-d6) δ 1.14-1.24 (2H, m), 1.35-1.47 (4H, m),1.54 (9H, s), 1.60-1.77 (2H, m), 3.54-3.58 (1H, m), 3.90 (3H, s), 7.71(2H, d), 8.11 (2H, d), 8.14 (1H, d)

MS m/z (ESI+) (M+H)+=403.

Intermediate #95 Methyl4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoate

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg,1.31 mmol) was added in one portion to1-(4-methoxycarbonylphenyl)-5-propylsulfanylpyrazole-4-carboxylic acid(Intermediate #7) (349 mg, 1.09 mmol),5-(difluoromethoxy)adamantan-2-amine (Intermediate #121) (260 mg, 1.20mmol), 1-Hydroxybenzotriazole (176 mg, 1.31 mmol) andN-Ethyldiisopropylamine (0.376 mL, 2.18 mmol) in DMF (10 mL). Theresulting mixture was stirred at 20° C. for 5 hours.

The reaction mixture was diluted with EtOAc (100 mL), and washedsequentially with water (4×25 mL) and saturated brine (25 mL). Theorganic layer was dried over MgSO4, filtered and evaporated to affordcrude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to afford methyl4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanyl-pyrazol-1-yl]benzoate(338 mg, 59.8%) as a white crystalline solid.

1H NMR (400.13 MHz, DMSO-d6) δ 0.68 (3H, t), 1.21-1.30 (2H, m), 1.51(2H, d), 1.90-1.97 (6H, m), 2.05 (2H, d), 2.15-2.20 (3H, m), 2.65 (2H,t), 3.91 (3H, s), 4.09 (1H, d), 6.88 (1H, t), 7.76-7.79 (2H, m), 7.98(1H, d), 8.13-8.16 (2H, m), 8.19 (1H, s)

m/z (ESI+) (M+H)+=520

Intermediate #96 methyl4-[4-(cyclohexylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate

To a solution of cyclopentyl mercaptan (0.071 ml, 0.66 mmol) in DMF (2ml) was added a 1N solution of NaHMDS in THF (0.66 ml, 0.66 mmol). Thereaction was stirred at ambient temperature for 2 minutes then added toa solution of methyl4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#15) (200 mg, 0.55 mmol) in to DMF (3 ml).

The reaction mixture was stirred at room temperature for two hours. Thereaction mixture was evaporated to dryness and redissolved in DCM (50mL) and washed with saturated NH₄Cl (10 mL), water (10 mL) and brine (10mL). It was dried over MgSO4 and the solvent was evaporated underreduced pressure to give a solid. The crude product was purified byflash silica chromatography, elution gradient 0 to 50% EtOAc inisohexane. Pure fractions were evaporated to dryness to afford methyl4-[4-(cyclohexylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate(233 mg, 98%) as a solid.

m/z (ESI+) (M+H)+=428

Intermediate #97 methyl4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanylpyrazol-1-yl]benzoate

Methyl4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanylpyrazol-1-yl]benzoate wasprepared from cyclohexylthiol and methyl4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#15) by the same process used for Intermediate #96.

m/z (ESI+) (M+H)+=442

Intermediate #98 methyl4-[5-cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate

Methyl4-[5-cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoatewas prepared from cycloheptylthiol and methyl4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#15) by the same process used for Intermediate #96.

m/z (ESI+) (M+H)+=456; HPLC t_(R)=3.27 min.

1H NMR (300.072 MHz, CDCl3) δ 1.08-1.48 (15H, m), 1.56-1.72 (5H, m),1.91-1.97 (2H, m), 2.84-2.93 (1H, m), 3.90 (3H, s), 3.93-4.02 (1H, m),7.57-7.65 (3H, m), 8.08-8.12 (2H, d), 8.22 (1H, s)

Intermediate #99 methyl4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoate

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (396 mg,2.07 mmol) was added in one portion to 2-Adamantanamine hydrochloride(324 mg, 1.72 mmol),5-(ethylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid (528 mg, 1.72 mmol) (Intermediate #101), 1-Hydroxybenzotriazole(279 mg, 2.07 mmol) and N-Ethyldiisopropylamine (0.885 mL, 5.17 mmol) inDMF (10 mL). The resulting mixture was stirred at 20° C. for 18 hours.

The reaction mixture was diluted with EtOAc (100 mL), and washedsequentially with water (4×25 mL) and saturated brine (25 mL). Theorganic layer was dried over MgSO4, filtered and evaporated to affordcrude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to afford methyl4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoate (430mg, 56.8%) as a white solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.94 (3H, t), 1.62 (2H, d), 1.74 (2H, s),1.86 (6H, d), 1.96-2.02 (4H, m), 2.68 (2H, q), 3.91 (3H, s), 4.11 (1H,t), 7.76-7.80 (2H, m), 8.04 (1H, d), 8.13-8.16 (2H, m), 8.20 (1H, s)

m/z (ESI+) (M+H)+=440

Intermediate #100 methyl4-[4-(2-adamantylcarbamoyl)-5-methylsulfanyl-pyrazol-1-yl]benzoate

Prepared from methyl4-[4-(2-adamantylcarbamoyl)-5-methylsulfanyl-pyrazol-1-yl]benzoate(Intermediate #102) by the same process as Intermediate #101.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.61 (2H, d), 1.74 (2H, s), 1.86 (6H, s),1.95-2.04 (4H, m), 2.29 (3H, s), 3.91 (3H, s), 4.11 (1H, t), 7.76-7.79(2H, m), 8.02 (1H, d), 8.13-8.16 (2H, m), 8.19 (1H, s)

m/z (ESI+) (M+H)+=426

Intermediate #1015-(ethylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid

Trifluoroacetic acid (1.324 mL, 17.24 mmol) was added to tert-butyl5-(ethylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #103) (625 mg, 1.72 mmol) in CH₂Cl₂ (25 mL) The resultingsolution was stirred at 20° C. for 24 hours.

The reaction mixture was evaporated to dryness and redissolved in dioxan(20 mL), and re-evaporated to dryness to afford5-(ethylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid (528 mg, 100%) as a white solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.96 (3H, t), 2.88 (2H, q), 3.91 (3H, s),7.70-7.74 (2H, m), 8.12-8.15 (2H, m), 8.19 (1H, s), 12.72 (1H, s)

m/z (ESI+) (M+H)+=307

Intermediate #1025-(methylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylicacid

Prepared from tert-butyl1-(4-(methoxycarbonyl)phenyl)-5-(methylthio)-1H-pyrazole-4-carboxylate(Intermediate #104) by the same process as Intermediate #101.

1H NMR (400.13 MHz, DMSO-d₆) δ 2.40 (3H, s), 3.90 (3H, d), 7.72-7.75(2H, m), 8.10-8.14 (2H, m), 8.17 (1H, s), 12.77 (1H, s)

m/z (ESI+) (M+H)+=293

Intermediate #103 tert-butyl5-(ethylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate

Sodium bis(trimethylsilyl)amide (3.56 mL, 3.56 mmol) was added dropwiseto ethanethiol (0.264 mL, 3.56 mmol) in DMF (10 mL) under nitrogen. Theresulting solution was stirred at 20° C. for 30 minutes. tert-butyl5-chloro-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #9) (1 g, 2.97 mmol) was added in one portion and theresulting suspension was stirred at 20° C. for 5 hours. The reactionmixture was diluted with EtOAc (100 mL), and washed sequentially withwater (4×25 mL), and saturated brine (25 mL). The organic layer wasdried over MgSO4, filtered and evaporated to afford crude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 30% EtOAc in isohexane. Product containing fractions wereevaporated to dryness to afford tert-butyl5-(ethylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(0.625 g, 58.1%) as a white crystalline solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.96 (3H, t), 1.55-1.56 (9H, m), 2.84(2H, q), 3.91 (3H, s), 7.70-7.73 (2H, m), 8.10-8.15 (3H, m)

m/z (ESI+) (M+H)+=363

Intermediate #104 tert-butyl1-(4-(methoxycarbonyl)phenyl)-5-(methylthio)-1H-pyrazole-4-carboxylate

Prepared from (Intermediate #9) and sodium methanethiolate by a similarprocess to that used for (Intermediate #103).

1H NMR (400.13 MHz, DMSO-d₆) δ 1.56 (9H, s), 2.38 (3H, s), 3.91 (3H, s),7.72-7.74 (2H, m), 8.10-8.17 (3H, m)

m/z (ESI+) (M+H)+=349

Intermediate #1054-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoicacid methyl ester

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg,0.66 mmol) was added to1-(4-(methoxycarbonyl)phenyl)-5-(propylthio)-1H-pyrazole-4-carboxylicacid (Intermediate #7) (152 mg, 0.47 mmol)5-Methanesulfonyl-adamantan-2-ylamine (Prepared by the method describedin Bioorganic & Medicinal Chemistry Letters 17 (2007) 527-532) (109 mg,0.47 mmol), 4-Dimethylaminopyridine (11.59 mg, 0.09 mmol) andTriethylamine (0.132 mL, 0.95 mmol) in DCM (7 mL) at ambient temperatureunder nitrogen. The resulting solution was stirred at ambienttemperature for 20 hours.

The reaction mixture was evaporated to dryness and redissolved in EtOAc(50 mL), and washed sequentially with 1N citric acid (25 mL), water (20mL), and saturated brine (20 mL). The organic layer was dried overMgSO4, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 20to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness toafford4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoicacid methyl ester (116 mg, 46.0%) as a white solid.

1H NMR (400.13 MHz, CDCl3) δ 0.76 (3H, t), 1.31-1.40 (2H, m), 1.71 (2H,d), 1.96 (2H, d), 2.11 (2H, s), 2.15-2.30 (5H, m), 2.33 (2H, s), 2.54(2H, t), 2.78 (3H, s), 3.97 (3H, s), 4.30-4.40 (1H, m), 7.71 (2H, d),8.07 (1H, d), 8.20 (2H, d), 8.30 (1H, s)

MS m/e MH⁺ 532.

Intermediate #106 methyl4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-2-methoxy-benzoate

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (197 mg,1.03 mmol) was added in one portion to 2-adamantanamine hydrochloride(161 mg, 0.86 mmol),1-(3-methoxy-4-(methoxycarbonyl)phenyl)-5-(propylthio)-1H-pyrazole-4-carboxylicacid (Intermediate #107) (300 mg, 0.86 mmol) 1-Hydroxybenzotriazole (139mg, 1.03 mmol) and N-Ethyldiisopropylamine (0.440 mL, 2.57 mmol) in DMF(10 mL). The resulting mixture was stirred at 20° C. for 18 hours.

The reaction mixture was diluted with EtOAc (100 mL), and washedsequentially with water (4×25 mL) and saturated brine (25 mL). Theorganic layer was dried over MgSO4, filtered and evaporated to affordcrude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to afford methyl4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-2-methoxy-benzoate(243 mg, 58.7%) as colourless oil.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.69 (3H, t), 1.24-1.32 (2H, m), 1.62(2H, d), 1.74 (2H, s), 1.86 (6H, d), 1.95-2.02 (4H, m), 2.65 (2H, t),3.83 (3H, s), 3.88 (3H, s), 4.11 (1H, d), 7.26-7.29 (1H, m), 7.44 (1H,d), 7.83 (1H, d), 8.09 (1H, d), 8.18 (1H, s)

m/z (ESI+) (M+H)+=484

Intermediate #1071-(3-methoxy-4-(methoxycarbonyl)phenyl)-5-(propylthio)-1H-pyrazole-4-carboxylicacid

Trifluoroacetic acid (1.194 mL, 15.55 mmol) was added to tert-butyl1-(3-methoxy-4-(methoxycarbonyl)phenyl)-5-(propylthio)-1H-pyrazole-4-carboxylate(Intermediate #108) (632 mg, 1.55 mmol) in CH₂Cl₂ (15 mL) The resultingsolution was stirred at 20° C. for 24 hours.

The reaction mixture was evaporated to dryness and re-dissolved indioxan (20 mL), and re-evaporated to dryness to afford1-(3-methoxy-4-(methoxycarbonyl)phenyl)-5-(propylthio)-1H-pyrazole-4-carboxylicacid (540 mg, 99%) as a colourless oil which solidified on standing.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.72 (3H, t), 1.25-1.34 (2H, m), 2.85(2H, t), 3.57 (1H, s), 3.83 (3H, s), 3.87 (3H, s), 7.19-7.22 (1H, m),7.36-7.36 (1H, m), 7.82 (1H, d), 8.18 (1H, s), 12.6 (1H, s)

m/z (ESI+) (M+H)+=351

Intermediate #108 tert-butyl1-(3-methoxy-4-(methoxycarbonyl)phenyl)-5-(propylthio)-1H-pyrazole-4-carboxylate

Sodium bis(trimethylsilyl)amide 1M solution in THF (3.60 mL, 3.60 mmol)was added dropwise to 1-propanethiol (0.326 mL, 3.60 mmol) in DMF (10mL) under nitrogen. The resulting solution was stirred at 20° C. for 30minutes. tert-butyl5-chloro-1-(3-methoxy-4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #109) (1.1 g, 3.00 mmol) was added as a solution in DMF (5mL) and the resulting mixture was stirred at 20° C. for 5 hours. Thereaction mixture was diluted with EtOAc (100 mL), and washedsequentially with water (4×25 mL), and saturated brine (25 mL). Theorganic layer was dried over MgSO4, filtered and evaporated to affordcrude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Product containing fractions wereevaporated to dryness to afford tert-butyl1-(3-methoxy-4-(methoxycarbonyl)phenyl)-5-(propylthio)-1H-pyrazole-4-carboxylate(0.642 g, 52.7%) as a colourless oil.

1H NMR (400.13 MHz, DMSO-d₆) δ 0.72 (3H, t), 1.29 (2H, q), 1.55 (9H, s),2.79 (2H, t), 3.83 (3H, s), 3.87 (3H, s), 7.19-7.22 (1H, m), 7.36 (1H,d), 7.82 (1H, d), 8.14 (1H, s)

m/z (ESI+) (M+H)+=407

Intermediate #109 tert-butyl5-chloro-1-(3-methoxy-4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate

Copper(II) chloride (0.917 g, 6.82 mmol) was added in one portion totert-Butyl nitrite (0.649 mL, 5.46 mmol) in acetonitrile (25 mL) at andwarmed to 50° C. The resulting mixture was stirred at 50° C. whiletert-butyl5-amino-1-(3-methoxy-4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #110) (1.58 g, 4.55 mmol) was added in portions as asolid. After the addition was complete the reaction mixture was stirredat 50° C. for 15 minutes and then cooled to 20° C. The reaction mixturewas diluted with EtOAc (100 mL), and washed sequentially with water(2×50 mL), and saturated brine (25 mL). The organic layer was dried overMgSO4, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 50% EtOAc in isohexane. Fractions were evaporated to dryness toafford tert-butyl5-chloro-1-(3-methoxy-4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(1.120 g, 67.1%) as a yellow oil.

1H NMR (400.13 MHz, DMSO-d₆) δ1.55 (9H, s), 3.83 (3H, s), 3.88 (3H, s),7.26-7.29 (1H, m), 7.42 (1H, d), 7.84 (1H, d), 8.20 (1H, s)

m/z (ESI+) (M+H)+=367

Intermediate #110 tert-butyl5-amino-1-(3-methoxy-4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate

Acetic anhydride (2.83 mL, 30.00 mmol) was added in one portion totert-Butyl cyanoacetate (4.29 mL, 30 mmol), and triethyl orthoformate(7.48 mL, 45.00 mmol). The resulting mixture was stirred at 125° C. for3 hours and then volatiles were removed by evaporation under reducedpressure. The resulting oil was dissolved in a ethanol (50 mL), treatedwith methyl 4-hydrazinyl-2-methoxybenzoate hydrochloride (Intermediate#111) (2.094 g, 9.00 mmol) and N-Ethyldiisopropylamine (1.572 mL, 9.00mmol) and stirred at 80° C. for 4 h.

The reaction mixture was concentrated and diluted with EtOAc (200 mL),and washed sequentially with water (2×100 mL), and saturated brine (50mL). The organic layer was dried over MgSO4, filtered and evaporated toafford crude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 50% EtOAc in isohexane. Purefractions were evaporated to dryness to afford tert-butyl5-amino-1-(3-methoxy-4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate(1.640 g, 52%) as an orange solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.52 (9H, s), 3.81 (3H, s), 3.89 (3H, s),6.47 (2H, s), 7.21-7.23 (1H, m), 7.30 (1H, d), 7.68 (1H, s), 7.81 (1H,d)

m/z (ESI+) (M+H)+=348

Intermediate #111 methyl 4-hydrazinyl-2-methoxybenzoate hydrochloride

tert-butyl 1-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate(Intermediate #112) (4.86 g, 16.40 mmol) was added to a 4M solution ofhydrogen chloride (61.5 mL, 246 mmol) in dioxane. The resulting solutionwas stirred at 20° C. for 5 hours. The reaction mixture was evaporatedto dryness and the crude residue was triturated with Et₂O to give asolid which was collected by filtration and dried under vacuum to givemethyl 4-hydrazinyl-2-methoxybenzoate hydrochloride (3.50 g, 92%) as apale green solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 3.73 (3H, s), 3.81 (3H, s), 6.53-6.56(1H, m), 6.79 (1H, d), 7.66 (1H, d), 8.79 (1H, s), 10.44 (3H, s)

m/z (ESI+) (M+H)+=197

Intermediate #112 tert-butyl1-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate

Copper(I) iodide (0.213 g, 1.12 mmol) was added to 1,10-Phenanthroline(0.403 g, 2.24 mmol), tert-Butyl carbazate (3.55 g, 26.83 mmol), cesiumcarbonate (10.20 g, 31.30 mmol) and methyl 4-iodo-2-methoxybenzoate(6.53 g, 22.36 mmol) in DMF (75 mL) under nitrogen. The resultingmixture was stirred at 100° C. for 1 hour. The reaction mixture wasdiluted with EtOAc (400 mL), and washed sequentially with water (4×100mL), and saturated brine (50 mL). The organic layer was dried overMgSO4, filtered and evaporated to afford crude product.

The crude product was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated todryness to afford tert-butyl1-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (4.86 g,73.4%) as a solid.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.50 (9H, s), 3.76 (3H, s), 3.80 (3H, s),5.11 (2H, s), 7.25-7.28 (1H, m), 7.39 (1H, d), 7.64 (1H, d)

m/z (ESI+) (M+H)+=297

Intermediate #113 Ethyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoate

N-(2-adamantyl)-1-(4-chloro-2-methyl-phenyl)-5-tert-butyl-pyrazole-4-carboxamide(Intermediate #114) (647 mg, 1.52 mmol), Molybdenum hexacarbonyl (0.102mL, 0.76 mmol), 4-Dimethylaminopyridine (371 mg, 3.04 mmol),N-Ethyldiisopropylamine (0.529 mL, 3.04 mmol),trans-Di-mu-acetatobis[2-(di-o-tolylphosphino)benzyl]dipalladium(II)(71.4 mg, 0.08 mmol) and Tri-tert-butylphosphine tetrafluoroborate (88mg, 0.30 mmol) were suspended in ethanol (6 mL) and dioxane (6.00 mL)and sealed into a microwave tube. The reaction was heated to 150° C. for1 hour in the microwave reactor and cooled to RT. The reaction mixturewas evaporated to dryness and redissolved in EtOAc (100 mL), and washedwith water (10 mL), filtered, then washed with 2M HCl (10 mL), andsaturated brine (10 mL). The organic layer was dried over MgSO4,filtered and evaporated to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 0 to 2.5%EtOAc in isohexane. Pure fractions were evaporated to dryness to affordethyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoate(352 mg, 50.0%) as a colourless oil.

m/z (ESI+) (M+H)+=3.22; HPLC t_(R)=464 min.

¹H NMR (300.072 MHz, cdcl3) δ 1.25 (s, 9H), 1.42 (t, 3H), 1.66-1.95 (m,12H), 2.01-2.10 (m, 2H), 2.13 (s, 3H), 4.22 (d, 1H), 4.41 (q, 2H), 6.14(d, 1H), 7.31 (d, 1H), 7.68 (s, 1H), 7.94 (d, 1H), 8.01 (s, 1H)

Intermediate #114N-(2-adamantyl)-1-(4-chloro-2-methyl-phenyl)-5-tert-butyl-pyrazole-4-carboxamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(Intermediate #115) (515 mg, 2.68 mmol) was added in one portion to2-Adamantanamine hydrochloride (420 mg, 2.24 mmol),5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylic acid(655 mg, 2.24 mmol), 1-Hydroxybenzotriazole (363 mg, 2.68 mmol) andN-Ethyldiisopropylamine (1.149 mL, 6.71 mmol) in DMF (10 mL). The isresulting mixture was stirred at 20° C. for 18 hours. The reactionmixture was diluted with Et₂O (100 mL), and washed sequentially withwater (3×25 mL), and saturated brine (25 mL). The organic layer wasdried over MgSO4, filtered and evaporated to afford desired productN-(2-adamantyl)-1-(4-chloro-2-methyl-phenyl)-5-tert-butyl-pyrazole-4-carboxamide(860 mg, 90%).

¹H NMR (300.072 MHz, cdcl3) δ 1.26 (s, 9H), 1.51-2.18 (m, 17H), 4.22 (d,1H), 6.12 (d, 1H), 7.17 (d, 1H), 7.25 (d, 1H), 7.31 (s, 1H), 7.65 (s,1H)

Intermediate #1155-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylic acid

5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylic acidwas prepared from ethyl5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylate(Intermediate #116) by the same process used for Intermediate #119.

¹H NMR (300.072 MHz, cdcl3) δ 1.30 (s, 9H), 2.04 (s, 3H), 7.15 (d, 1H),7.26 (d, 1H), 7.31 (s, 1H), 8.16 (s, 1H)

m/z (ESI+) (M+H)+=293

Intermediate #116 Ethyl5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylate

N-Ethyldiisopropylamine (1.553 mL, 8.97 mmol) was added to(4-chloro-2-methylphenyl)hydrazine hydrochloride (1.733 g, 8.97 mmol)and (Z)-ethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopentanoate(Intermediate #83) (2.04 g, 8.97 mmol) in ethanol (30 mL). The resultingsolution was stirred at 90° C. for 2 hours. The reaction mixture wasevaporated to dryness and redissolved in DCM (50 mL), and washedsequentially with water (2×10 mL). The organic layer was dried overMgSO4, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness toafford ethyl5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylate(0.891 g, 30.9%) as a orange oil.

¹H NMR (300.072 MHz, cdcl3) δ 1.29 (s, 9H), 1.38 (t, 3H), 2.03 (s, 3H),4.31 (q, 2H), 7.14 (d, 1H), 7.23 (d, 1H), 7.29 (d, 1H), 8.04 (s, 1H)

m/z (ESI+) (M+H)+=321

Intermediate #117 Ethyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoate

Ethyl4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoatewas prepared fromN-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]-5-tert-butyl-pyrazole-4-carboxamide(Intermediate #118) by the same process used for Intermediate #113.

¹H NMR (300.072 MHz, CDCl₃) δ 1.27-1.33 (9H, m), 1.42 (3H, t), 1.74-1.79(5H, m), 1.85-1.91 (7H, m), 2.06 (2H, s), 4.23 (1H, d), 4.44 (2H, q),6.13 (1H, d), 7.62 (1H, d), 7.62 (1H, t), 7.75-7.76 (1H, m), 7.92 (1H,d)

m/z (ESI+) (M+H)+=518

Intermediate #118N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]-5-tert-butyl-pyrazole-4-carboxamide

N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]-5-tert-butyl-pyrazole-4-carboxamidewas prepared from5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylicacid (Intermediate #119) by the same process used for Intermediate #114.

¹H NMR (300.072 MHz, cdcl3) δ 1.29 (s, 9H), 1.55-1.97 (m, 12H), 2.06 (s,2H), 4.22 (d, 1H), 6.12 (d, 1H), 7.48 (d, 1H), 7.62 (d, 1H), 7.63 (s,1H), 7.71 (s, 1H)

m/z (ESI+) (M+H)+=480

Intermediate #1195-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylicacid

A solution of Sodium hydroxide (6.67 mL, 13.34 mmol) was added in oneportion to a stirred solution of ethyl5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate(Intermediate #120) (1 g, 2.67 mmol) in methanol (20 mL). The resultingsuspension was stirred at 80° C. for 6 hours. The resulting mixture wasevaporated to remove the methanol, washed with ether (20 mL). Thereaction mixture was acidified with 2M HCl, extracted with ethyl acetate(2×30 mL) The organic layers were combined and washed with water (10 mL)and brine (10 mL), dried over MgSO4, filtered and evaporated to affordpure5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylicacid (0.766 g, 83%).

¹H NMR (300.072 MHz, cdcl3) δ 1.36 (s, 9H), 7.47 (d, 1H), 7.63 (d, 1H),7.70 (s, 1H), 8.12 (s, 1H)

m/z (ESI+) (M+H)+=345

Intermediate #120 Ethyl5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate

Ethyl5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylatewas prepared from (Z)-ethyl2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopentanoate (Intermediate#83) and (4-chloro-3-(trifluoromethyl)phenyl)hydrazine hydrochloride bythe same process used for Intermediate #116.

¹H NMR (300.072 MHz, cdcl3) δ 1.32 (s, 9H), 1.38 (t, 3H), 4.32 (q, 2H),7.46 (d, 1H), 7.61 (d, 1H), 7.68 (s, 1H), 7.98 (s, 1H)

m/z (ESI+) (M+H)+=375

Intermediate #121 (1R,2S,3S,5S)-5-Difluoromethoxy-adamantan-2-ylamine

((1R,2S,3S,5S)-5-Difluoromethoxy-adamantan-2-yl)-carbamic acid benzylester (Intermediate #122) (255 mg, 0.73 mmol) and Palladium (10% oncarbon) (25 mg, 0.23 mmol) in MeOH (5 mL) were stirred under anatmosphere of hydrogen at 1 atm and ambient temperature for 22 hours.The reaction mixture was filtered through celite and the solvent wasevaporated in vacuo to yield(1R,2S,3S,5S)-5-Difluoromethoxy-adamantan-2-ylamine (130 mg, 82%) as aclear oil.

1H NMR (400.13 MHz, CDCl₃) δ 1.38-1.44 (5H, m), 1.91-2.00 (9H, m), 2.14(1H, s), 3.05 (1H, s), 6.15-6.54 (1H, t)

m/z (ESI+) (M+H)+=218

Intermediate #122((1R,2S,3S,5S)-5-Difluoromethoxy-adamantan-2-yl)-carbamic acid benzylester

Solution of 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (0.237 mL, 2.30mmol) in acetonitrile (2 mL; was added dropwise to a stirred solution of((1R,2S,3S,5S)-5-Hydroxy-adamantan-2-yl)-carbamic acid benzyl ester (346mg, 1.15 mmol) and Copper(I) iodide (7.78 μL, 0.23 mmol) in acetonitrile(10 mL) at 45° C., over a period of 1 hour under nitrogen. The resultingsolution was stirred at 45° C. for 15 minutes. The reaction mixture wasevaporated to dryness and redissolved in EtOAc (50 mL), and washedsequentially with water (50 mL) and saturated brine (25 mL). The organiclayer was dried over MgSO4, filtered and evaporated to afford crudeproduct. The crude product was purified by flash silica chromatography,elution gradient 0 to 30% EtOAc in isohexane. Pure fractions wereevaporated to dryness to afford((1R,2S,3S,5S)-5-Difluoromethoxy-adamantan-2-yl)-carbamic acid benzylester (269 mg, 66.7%) as a colourless oil.

1H NMR (400.13 MHz, DMSO-d6) δ 1.35 (2H, d), 1.86 (4H, d), 1.94 (4H, t),2.06 (3H, s), 3.65 (1H, m), 5.04 (2H, s), 6.65-7.03 (1H, t), 7.29-7.42(6H, m)

Intermediate #123 methyl 4-hydrazinylbenzoate hydrochloride

Hydrogen chloride 4M in Dioxan (100 mL, 399.60 mmol) was added to4-Hydrazinobenzoic acid (15.2 g, 99.90 mmol) in MeOH (200 mL). Theresulting suspension was stirred at 90° C. for 5 hours. After cooling to20° C. the precipitate was collected by filtration, washed with Et₂O(100 mL) and dried under vacuum to afford2-(4-(methoxycarbonyl)phenyl)hydrazinium chloride (16.50 g, 82%) as acream crystalline solid.

m/z (ESI−) (M−H)-=165; HPLC t_(R)=1.12 min.

1H NMR (400.13 MHz, DMSO-d6) δ 3.81 (3H, s), 6.99-7.02 (2H, m),7.86-7.90 (2H, o10 m), 8.98 (1H, s), 10.47 (3H, s)

Intermediate #123 may also be prepared as follows:

Methanolic hydrochloric acid solution (4M) (4 equiv., freshly prepared)was added to a suspension of 4-hydrazinobenzoic acid (1 equiv.) inmethanol (12.6 vols.), under nitrogen.

The mixture was stirred under reflux for three hours and then cooled tobelow 15

C. The solid was collected by filtration, washed with MTBE (6.5 vols.)and dried in air to give the product as a solid.

TLC DCM:MeOH, 9:1, Product R_(f) 0.87

mp 233.8-234.6 C

Intermediate #124N-adamantan-2-yl-1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

2-Adamantanamine hydrochloride (0.375 g, 2.00 mmol) was added in oneportion to1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid(Intermediate #125) (0.562 g, 2 mmol), 1-Hydroxybenzotriazole (0.297 g,2.20 mmol), N-Ethyldiisopropylamine (1.384 mL, 8.00 mmol) and1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.460 g,2.40 mmol) in DMF (10 mL) under nitrogen.

The resulting solution was stirred at room-temperature for 16 hours. Thereaction mixture was poured onto water (75 mL), extracted with EtOAc(2×50 mL), the organic layer was dried over MgSO4, filtered andevaporated to afford beige solid. The crude product was purified byflash silica chromatography, elution gradient 20 to 60% EtOAc in toisohexane. Pure fractions were evaporated to dryness to affordN-adamantan-2-yl-1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide(0.480 g, 57.9%) as a white solid.

m/z (ESI+) (M+H)+=415; HPLC t_(R)=2.82 min.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.51 (2H, d), 1.70 (2H, s), 1.81 (5H, s),1.84 (1H, s), 1.92 (2H, s), 2.04 (2H, d), 4.01 (1H, t), 7.73 (2H, d),8.08-8.11 (2H, m), 8.18 (1H, s), 8.34 (1H, d).

Intermediate #1251-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

Potassium trimethylsilanolate (3.32 g, 23.28 mmol) was added in oneportion to ethyl1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate(Intermediate #126) (2.4 g, 7.76 mmol), in THF (50 mL), under nitrogen.The resulting suspension was stirred at room temperature for 3 hours.The reaction mixture was evaporated to dryness and redissolved in EtOAc(100 mL), and washed sequentially with 0.1M HCl (50 mL), water (50 mL),and saturated brine (50 mL). The organic layer was dried over MgSO4,filtered and evaporated to afford crude product. The crude solid wastriturated with isohexane to give a solid which was collected byfiltration and dried under vacuum to give1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid(1.600 g, 73.3%) as a orange solid. Used directly in next stage.

m/z (ESI+) (M−H)-=280; HPLC t_(R)=1.86 min.

1H NMR (400.13 MHz, DMSO-d₆) δ 7.78-7.80 (2H, m), 8.07-8.10 (2H, m),8.26 (1H, s), 13.39 (1H, s)

Intermediate #126 Ethyl1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

A solution of (Z)-ethyl2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (2.41 g, 10.03 mmol)in ethanol (10 mL) was added dropwise to a stirred solution of4-hydrazinylbenzonitrile hydrochloride (1.702 g, 10.03 mmol), in ethanol(50 mL) cooled to −10° C. The resulting solution was allowed to stir atroom temperature for 16 hours. The reaction mixture was evaporated todryness and the residue redissolved in EtOAc (100 mL), and washedsequentially with water (50 mL) and saturated brine (50 mL). The organiclayer was dried over MgSO4, filtered and evaporated to afford crudeproduct. The crude product was purified by flash silica (120 g)chromatography, elution gradient 10 to 60% EtOAc in isohexane. Purefractions were evaporated to dryness to afford ethyl1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.400g, 77%) as a white solid.

m/z (ESI+) (M+H)+=310; HPLC t_(R)=2.51 min.

1H NMR (400.13 MHz, DMSO-d₆) δ 1.31 (3H, t), 4.33 (2H, q), 7.81-7.84(2H, m), 8.10-8.13 (2H, m), 8.38-8.38 (1H, m)

1. A compound of the formula (1):

wherein: Q is O, S or a single bond; R¹ is C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₇cycloalkyl, heterocyclyl, arylC₁₋₃alkyl,heteroarylC₁₋₃alkyl, C₃₋₇cycloalkylC₁₋₃alkyl, C₃₋₇cycloalkylC₂₋₃alkenylor C₃₋₇cycloalkylC₂₋₃alkynyl, [each of which is optionally substitutedby 1, 2 or 3 substituents independently selected from C₁₋₃alkyl,hydroxy, halo, oxo, cyano, trifluoromethyl, C₁₋₃alkoxy,C₁₋₃alkylS(O)_(n)— (wherein n is 0, 1, 2 or 3), R⁵CON(R^(5′))—,(R^(5′))(R⁵″)NC(O)—, R^(5′)C(O)O—, R^(5′)OC(O)—,(R^(5′))(R^(5″))NC(O)N(R^(5′″))—, R⁵SO₂N(R⁵″)—, and (R^(5′))(R⁵″)NSO₂—(wherein R⁵ is C₁₋₃alkyl optionally substituted by 1, 2 or 3substituents selected from hydroxyl, halo or cyano; and R^(5′) andR^(5″) are independently selected from hydrogen and C₁₋₃alkyl optionallysubstituted by 1, 2 or 3 substituents independently selected fromhydroxyl, halo, C₁₋₃alkoxy, carboxy and cyano or R^(5′) and R^(5″)together with the nitrogen atom to which they are attached form a 4-7membered saturated ring)]; R² is selected from heterocyclyl,C₃₋₇cycloalkyl(CH₂)_(m)—, and C₆₋₁₂polycycloalkyl(CH₂)_(m)— (wherein mis 0, 1 or 2 and the rings are optionally substituted by 1, 2 or 3substituents independently selected from R⁶); R³ is selected fromhydrogen, C₁₋₄alkyl C₃₋₅cycloalkyl and C₃₋₅cycloalkylmethyl (each ofwhich is optionally substituted by 1, 2 or 3 fluoro atoms); R² and R³together with the nitrogen atom to which they are attached form asaturated mono, bicyclic or bridged ring system optionally containing 1or 2 additional ring heteroatoms selected from nitrogen, oxygen andsulphur and which is optionally fused to a saturated, partiallysaturated or unsaturated monocyclic ring wherein the resulting ringsystem is optionally substituted by 1, 2, or 3 substituentsindependently selected from R⁷; R⁶ and R⁷ are independently selectedfrom hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, R⁹, R⁹O—,R⁹CO—, R⁹C(O)O—, R⁹CON(R^(9′))—, (R^(9′))(R⁹″)NC(O)—, (R^(9′))(R⁹″)N—,R⁹S(O)_(a)— wherein a is 0 to 2, R^(9′)OC(O)—, (R^(9′))(R⁹″)NSO₂—,R⁹SO₂N(R^(9″))—, (R^(9′))(R^(9″))NC(O)N(R^(9′″))—, phenyl and heteroaryl[wherein the phenyl and heteroaryl groups are optionally fused to aphenyl, heteroaryl or a saturated or partially-saturated 5- or6-membered ring optionally containing 1, 2 or 3 heteroatomsindependently selected from nitrogen, oxygen and sulphur and theresulting ring system is optionally substituted by 1, 2 or 3substituents independently selected from C₁₋₄alkyl, hydroxyl, cyano,trifluoromethyl, trifluoromethoxy, halo, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, amino, N—C₁₋₄alkylamino, di-N,N—(C₁₋₄alkyl)amino,N—C₁₋₄alkylcarbamoyl, di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(r)—,C₁₋₄alkylS(O)_(r)C₁₋₄alkyl (wherein r is 0, 1 or 2)]; R⁹ isindependently selected from C₁₋₃alkyl optionally substituted byhydroxyl, halo, C₁₋₄alkoxy, carboxy or cyano; R^(9′), R^(9″) and R^(9′″)are independently selected from hydrogen and C₁₋₃alkyl optionallysubstituted by 1, 2, or 3 substituents independently selected fromhydroxyl, halo, C₁₋₄alkoxy, carboxy and cyano); A is a phenyl orheteroaryl ring (the phenyl or heteroaryl ring being optionallysubstituted on ring carbon atoms by 1, 2 or 3 R¹⁰ groups and on anavailable ring nitrogen in a heteroaryl group by R¹¹); R¹⁰ isindependently selected from C₁₋₄alkyl, hydroxyl, cyano, trifluoromethyl,trifluoromethoxy, halo, C₁₋₄alkoxy, C₄ alkoxyC₁₋₄alkyl, amino,N—C₁₋₄alkylamino, di-N,N—(C₁₋₄alkyl)amino, N—C₁₋₄alkylcarbamoyl,di-N,N—(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylS(O)_(s)—,C₁₋₄alkylS(O)_(s)C₁₋₄alkyl (wherein s is 0, 1 or 2)]; R¹¹ isindependently C₁₋₃alkyl optionally substituted by 1, 2 or 3 fluoroatoms; X is a direct bond, C₃₋₄cycloalkandiyl, C₃₋₄cycloalkanylidene,—C(R¹²)(R¹³)—, —C(R¹²)(R¹³)C(R¹⁴)(R¹⁵)—, —CH₂O— or —CH₂S(O)_(t)—(wherein t is 0, 1 or 2): Y is a direct bond, C₃₋₄cycloalkandiyl,C₃₋₄cycloalkanylidene, —C(R¹⁶)(R⁷)— or —C(R¹⁸)(R¹⁹)C(R²⁰)(R²¹)—; whereinR¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are independentlyselected from hydrogen and methyl; or a pharmaceutically-acceptable saltthereof.
 2. A compound according to claim 1 wherein Q is S.
 3. Acompound according to claim 1 wherein Q is a single bond.
 4. A compoundaccording to any one of claims 1 to 3 wherein R² is selected fromC₅₋₇cycloalkyl(CH₂)_(m)—, C₇₋₁₀bicycloalkyl(CH₂)_(m)— andC₁₀tricycloalkyl(CH₂)_(m)— (wherein the cycloalkyl, bicycloalkyl andtricycloalkyl rings are optionally substituted by 1, 2 or 3 substituentsindependently selected from R⁶ wherein R⁶ is as defined in claim 1) andwherein m is 0, 1 or 2 and R³ is hydrogen.
 5. A compound according toany one of claims 1 to 4 wherein X is a direct bond.
 6. A compoundaccording to any one of claim 1 to 5 wherein Y is selected from directbond, —CH₂— and —CH₂CH₂—.
 7. A compound according to claim 1 of theformula (Ia):

wherein R¹, R² and R³ are as defined in claim 1 and R¹⁰ is selected fromhydrogen, C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy and C₁₋₄alkylS—; or apharmaceutically-acceptable salt thereof.
 8. A compound according toclaim 1 of the formula (Ib):

wherein R¹, R² and R³ are as defined in claim 1 and R¹⁰ is selected fromhydrogen, C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy and C₁₋₄alkylS—; or apharmaceutically-acceptable salt thereof.
 9. A compound according toclaim 1 selected from:4-[4-[[(1S,3R)-5-hydroxy-2-adamantyl]carbamoyl]-5-propylsulfanyl-pyrazol-1-yl]benzoicacid; 4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoicacid; 4-[4-(1-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoicacid;4-[4-(N-cyclohexyl-N-methyl-carbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoicacid; 4-[4-(oxan-4-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoicacid;4-[5-propylsulfanyl-4-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl]pyrazol-1-yl]benzoicacid; 4-[4-(cyclohexylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoicacid; 4-[4-(2-adamantylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoicacid; 4-[4-(1-adamantylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoicacid;4-[4-(cyclohexyl-methyl-carbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoicacid;4-[5-cyclopropyl-4-[(4-hydroxy-1-adamantyl)carbamoyl]pyrazol-1-yl]benzoicacid;2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]aceticacid;2-[4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]aceticacid;4-(4-cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoicacid;3-(4-cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoicacid;3-[4-(adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-ylmethyl]-benzoicacid;4-[4-(adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-ylmethyl]-benzoicacid; 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoicacid;4-[4-(2-adamantylcarbamoyl)-5-(1-methylcyclopropyl)pyrazol-1-yl]benzoicacid; 4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoicacid; 4-[4-(2-adamantylcarbamoyl)-5-ethylpyrazol-1-yl]benzoic acid;4-[4-(2-adamantylcarbamoyl)-5-propan-2-ylpyrazol-1-yl]benzoic acid;4-[4-(2-adamantylcarbamoyl)-5-cyclobutylpyrazol-1-yl]benzoic acid;4-[4-(2-adamantylcarbamoyl)-5-methyl-pyrazol-1-yl]benzoic acid;4-(5-tert-butyl-4-(cyclohexylcarbamoyl)-1H-pyrazol-1-yl)benzoic acid;4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoicacid;4-[4-(1-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoicacid;4-[5-cyclohexylsulfanyl-4-[(5-hydroxy-2-adamantyl)carbamoyl]pyrazol-1-yl]benzoicacid;4-[5-cyclohexylsulfanyl-4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]pyrazol-1-yl]benzoicacid;4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoicacid; methyl4-[4-(1-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate;methyl4-[5-cyclopentylsulfanyl-4-[[(1R,3S)-5-hydroxy-2-adamantyl]carbamoyl]pyrazol-1-yl]benzoate;4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoicacid;4-[4-(cyclohexylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoicacid;4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoicacid;4-[5-cyclohepylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoicacid; 4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoicacid; 4-[4-(2-adamantylcarbamoyl)-5-methylsulfanyl-pyrazol-1-yl]benzoicacid;4-[4-(5-methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoicacid;4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-2-methoxy-benzoicacid;4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoicacid;4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoicacid; and4-[4-(adamantan-2-ylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzoicacid; and pharmaceutically-acceptable salts thereof.
 10. Apharmaceutical composition, which comprises a compound of formula (I),or a pharmaceutically acceptable salt thereof, as claimed in claim 1 inassociation with a pharmaceutically-acceptable diluent or carrier.
 11. Acompound of formula (1), or a pharmaceutically acceptable salt thereof,as claimed in claim 1, for use in a method of prophylactic ortherapeutic treatment of a warm-blooded animal, such as man.
 12. Acompound of formula (1), or a pharmaceutically acceptable salt thereof,as claimed in claim 1 for use as a medicament.
 13. The use of a compoundof formula (1), or a pharmaceutically acceptable salt thereof, asclaimed in claim 1 in the manufacture of a medicament for use in theproduction of an 11βHSD1 inhibitory effect in a warm-blooded animal,such as man.
 14. A process for preparing a compound of the formula (1)or a pharmaceutically acceptable salt thereof which process comprisesany one of processes a) or b): a) hydrolysis of an ester of formula (2):

 wherein R²² is an alkyl or aryl group; or b) converting Z in a compoundof the formula (3):

 into a carboxy group, wherein Z is an functional group capable ofconversion into a carboxylic acid; and thereafter if necessary ordesirable: i) converting a compound of the formula (1) into anothercompound of the formula (1); ii) removing any protecting groups; iii)resolving enantiomers; iv) forming a pharmaceutically-acceptable saltthereof.